7-membered ring compound and method of production and pharmaceutical application thereof

ABSTRACT

A 7-membered heterocyclic compound having the formula (I), or its salt, or a solvate thereof with a chymase inhibitory action and useful for the prevention or treatment of various diseases, in which chymase is involved: 
     
       
         
         
             
             
         
       
     
     a method for producing the same, and a pharmaceutical composition useful for the prevention or treatment of diseases, in which chymase is involved, including the compound of having the formula (I), or its pharmaceutically acceptable salt, or a solvate thereof are provided.

TECHNICAL FIELD

The present invention relates to a 7-membered ring compound having achymase inhibitory activity and useful as a pharmaceutical for theprevention and/or treatment of diseases, in which chymase is involved,such as bronchial asthma, urticaria, atopic dermatitis, allergicconjunctivitis, rhinitis, rheumatoid arthritis, mastocytosis,scleroderma, heart failure, cardiac hypertrophy, congestive heartfailure, hypertension, atherosclerosis, myocardial ischemia, myocardialinfarction, restenosis after PTCA, restenosis after bypass graftsurgery, ischemic peripheral circulatory disorders, hyperaldosteronism,diabetic retinopathy, diabetic nephropathy, nephritis,glomerulosclerosis, renal insufficiency, psoriasis, solid tumor,postoperative adhesion, glaucoma, and ocular hypertension, and themethod of production thereof and starting compounds useful for the same.

BACKGROUND ART

Chymase is stored as an ingredient in granules of mast cells (MC), whichare one of the inflammatory cells closely related to inflammation, andis widely present mainly in the tissue such as skin, heart, vascularwalls, intestines etc. (see Non-Patent Document 1). Human chymase isknown as an enzyme for specifically producing angiotensin II (i.e., AngII) from angiotensin I (i.e., Ang I) independently from angiotensinconverting enzyme. There is a report that, in human cardiac tissue, 80%of the production of angiotensin II is derived from by chymase (seeNon-Patent Document 2). Ang II is known to be closely related toregulation of the blood pressure, diuretic regulation, and hypertrophyand remodeling of the cardiovascular system, that is, the migration andproliferation of smooth muscle cells etc. and the growth of theextracellular matrix in the cardiovascular system tissue. From thesefindings, it is suggested that chymase is closely related tocardiovascular lesions through production of Ang II. In addition toproduction of Ang II, it is reported that chymase has the followingactions based on its protease activity: 1) degradation of theextracellular matrix (see Non-Patent Document 3), activation ofcollagenase (see Non-Patent Document 4), and production of collagen (seeNon-Patent Document 5); 2) processing and activation of inflammatorycytokine, for example, release of latent TGF β1 from extracellularmatrix (see Non-Patent Document 6), activation of latent TGFβ1 to activeTGFβ1 (see Non-Patent Document 7), and activation of IL-1β (seeNon-Patent Document 8); 3) activation of stem cell factor (SCF) whichinduces differentiation and proliferation of MCs (see Non-PatentDocument 9); 4) degradation of apolipoprotein B in LDL (see Non-PatentDocument 10) and degradation of apolipoprotein A in HDL (see Non-PatentDocument 11); and 5) conversion of big endothelin to a bioactive peptidecomprised of 31 amino acid residues (ET(1-31)) (see Non-Patent Document12). Further, it is reported that chymase stimulates rat peritoneal mastcells to induce degranulation (see Non-Patent Document 13) and thatadministration of human chymase intraperitoneally to mice orsubcutaneously to guinea pigs induces infiltration of eosinophil andother leukocytes (see Non-Patent Document 14), and causes continuousincrease of vascular permeability not through the action of histamine(see Non-Patent Document 15). These various reports relating to theaction of chymase suggest that chymase plays an important role in theprocesses of tissue inflammation, repair, and healing, and in allergicconditions. It is believed that in these processes, the excessivereaction of chymase is involved in various diseases.

From the above-mentioned findings, a chymase inhibitor can be expectedto be useful as a pharmaceutical for the prevention or treatment of forexample, bronchial asthma, urticaria, atopic dermatitis, allergicconjunctivitis, rhinitis, rheumatoid arthritis, mastocytosis,scleroderma, heart failure, cardiac hypertrophy, congestive heartfailure, hypertension, atherosclerosis, myocardial ischemia, myocardialinfarction, restenosis after PTCA, restenosis after bypass graftsurgery, ischemic peripheral circulatory disorders, hyperaldosteronism,diabetic retinopathy, diabetic nephropathy, nephritis,glomerulosclerosis, renal insufficiency, psoriasis, solid tumor,postoperative adhesion, glaucoma, and ocular hypertension, and otherdiseases.

On the other hand, small molecule chymase inhibitors are already shownin books (see Non-Patent Document 16) or review articles (see Non-PatentDocuments 17, 18, and 19). The efficacy of several inhibitors amongthese in animal disease models has been reported (vascular lipiddeposition: see Patent Document 1, heart failure: see Non-PatentDocument 20, myocardial infarction: see Patent Document 2, seeNon-Patent Document 21, see Non-Patent Document 22, aortic aneurysm: seePatent Document 3, restenosis: see Patent Document 4, atopic dermatitis:see Patent Document 5, pruritus: see Patent Document 6, eosinphilia: seePatent Document 7, fibrosis: see Patent Document 8). Further, recently,in addition to the chymase inhibitors described in the above-mentionedbooks and review articles, imidazolidinedione derivatives (see PatentDocument 9), phosphonic acid derivatives (see Patent Document 10),benzothiophensulfonamide derivatives (see Patent Document 11), imidazolederivatives (see Patent. Document 12), triazolidine derivatives (seePatent Document 13), pyridone derivatives (see Patent Document 14),thiazolimine and oxazolimine derivatives (see Patent Document 15), andenamide derivatives (see Patent Document 16) are disclosed as novelchymase inhibitors. However, there are no examples of the above chymaseinhibitors being practically used as pharmaceuticals.

Further, 1,4-diazepan-2,5-dione skeleton compounds similar in structureto the present invention are disclosed in documents (see Non-PatentDocuments 23 and 24) etc., but none has the electron withdrawing groupsuch as a carbonyl group, sulfonyl group, or other electron withdrawinggroup at the 4-position nitrogen atom like in the present invention.Further, there is no disclosure at all of chymase inhibitory activitylike in the present invention. Further, Patent Document 17 andNon-Patent Document 25 disclose a 1,4-benzodiazepine derivative as a7-membered lactam derivative having a carbonyl group, sulfonyl group, orother electron withdrawing group at the 4-position nitrogen atom, butthese derivatives differ in skeleton from the present invention.Further, there is no disclosure at all of chymase inhibitory activitylike in the present invention.

Further, as examples of production of a non-fused 1,4-diazepan-2,5-dionederivative similar to the present invention, a 7-membered ring closurereaction using lactamization etc. are reported in Non-Patent Documents26 and 27. However, up to now, there has been no report of a productionmethod characterized by introducing an electron withdrawing group at the4-position nitrogen atom of a 1,4-diazepan-2,5-dione derivative, like inthe present invention. Further, there has been no report up to now of aproduction method of 1,4-diazepan-2,5-dione derivative characterized byan intramolecular alkylation reaction at the portions corresponding tothe 4-position nitrogen atom and 3-position carbon atom, like in thepresent invention.

-   [Patent Document 1] WO01-32214-   [Patent Document 2] WO03-07964-   [Patent Document 3] WO03-07964-   [Patent Document 4] WO02-32881-   [Patent Document 5] WO01-62294-   [Patent Document 6] WO00-51640-   [Patent Document 7] WO00-162293-   [Patent Document 8] WO00-162292-   [Patent Document 9] WO02-83649-   [Patent Document 10] WO03-35654-   [Patent Document 11] WO03-78419-   [Patent Document 12] WO04-07464-   [Patent Document 13] Japanese Patent Publication (A) No. 2003-342265-   [Patent Document 14] Japanese Patent Publication (A) No. 2004-67584-   [Patent Document 15] WO05-000825-   [Patent Document 16] WO05-073214-   [Patent Document 17] DE 2257171-   [Non-Patent Document 1] Mast Cell Proteases in Immunology and    Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.: New York, 1995-   [Non-Patent Document 2] J. Biol. Chem., 1990, 265(36), 22348-   [Non-Patent Document 3] J. Biol. Chem., 1981, 256(1), 471-   [Non-Patent Document 4] J. Biol. Chem., 1994, 269(27), 18134-   [Non-Patent Document 5] J. Biol. Chem., 1997, 272(11), 7127-   [Non-Patent Document 6] J. Biol. Chem., 1995, 270(9), 4689-   [Non-Patent Document 7] FASEB J., 2001, 15(8), 1377-   [Non-Patent Document 8] J. Exp. Med., 1991, 174(4), 821-   [Non-Patent Document 9] Proc. Natl. Acad. Sci. USA., 1997, 94(17),    901.7-   [Non-Patent Document 10] J. Biol. Chem., 1986, 261(34), 16067-   [Non-Patent Document 11] J. Clin. Invest., 1996, 97(10), 2174-   [Non-Patent Document 12] J. Immunol., 1997, 159(4), 1987-   [Non-Patent Document 13] J. Immunol., 1986, 136(10), 3812-   [Non-Patent Document 14] Br. J. Pharmacol., 1998, 125(7), 1491-   [Non-Patent Document 15] Eur. J. Pharmacol., 1998, 352(1), 91-   [Non-Patent Document 16] Protease Inhibitors; Barrett et. al., Eds;    Elsevier Science B.V.: Amsterdam, 1986-   [Non-Patent Document 17] Curr. Pharm. Des., 1998, 4(6), 439-   [Non-Patent Document 18] Exp. Opin. Ther. Patents, 2001, 11, 1423-   [Non-Patent Document 19] Idrugs, 2002, 5(12), 1141-   [Non-Patent Document 20] Circulation, 2003, 107(20), 2555-   [Non-Patent Document 21] Life Sci., 2002, 71(4), 437-46-   [Non-Patent Document 22] J. Pharmacol. Sci., 2004, 94(4), 443

[Non-Patent Document 23] J. Org. Chem., 2003, 68(20), 7893

-   [Non-Patent Document 24] J. Pept. Sci. 2003, 9(3), 187-   [Non-Patent Document 25] J. Org. Chem., 1980, 45(9), 1675-   [Non-Patent Document 26] J. Org. Chem., 2003, 68(20), 7893-   [Non-Patent Document 27] J. Pept. Sci. 2003, 9(3), 187

DISCLOSURE OF THE INVENTION

As explained above, at present, several types of small molecule chymaseinhibitors have been disclosed. However, up until now, no clinicallyapplicable chymase inhibitors have been found. Development of aclinically applicable chymase inhibitor leading to the prevention ortreatment of bronchial asthma, urticaria, atopic dermatitis, allergicconjunctivitis, rhinitis, rheumatoid arthritis, mastocytosis,scleroderma, heart failure, cardiac hypertrophy, congestive heartfailure, hypertension, atherosclerosis, myocardial ischemia, myocardialinfarction, restenosis after PTCA, restenosis after bypass graftsurgery, ischemic peripheral circulatory disorders, hyperaldosteronism,diabetic retinopathy, diabetic nephropathy, nephritis,glomerulosclerosis, renal insufficiency, psoriasis, solid tumor,postoperative adhesion, glaucoma, and ocular hypertension, and otherdiseases in which chymase is involved is therefore desired.

To solve this issue, the present invention provides a compound havingthe following formula (I) characterized in chemical structure with a7-membered ring skeleton:

wherein, Ar indicates (1) a C₆ to C₁₄ aromatic hydrocarbon group, (2) a5- to 8-membered aromatic heterocyclic group including 1 to 4 heteroatoms selected from a nitrogen atom, sulfur atom, and oxygen atom, otherthan a carbon atom, or (3) a bicyclic or tricyclic aromatic group formedby condensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon ring,

-   -   wherein, the groups (1) to (3) of the above Ar may optionally be        substituted with any 1 to 5 groups selected from the group        consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv)        C₁ to C₆ alkyl which may optionally be substituted with 1 to 3        halogen atoms, (v) C₂ to C₆ alkenyl which may optionally be        substituted with 1 to 3 halogen atoms, (vi) C₂ to C₆ alkynyl        which may optionally be substituted with 1 to 3 halogen        atoms, (vii) C₃ to C₆ cycloalkyl, (viii) hydroxyl, (ix) C₁ to C₆        alkoxy which may optionally be substituted with 1 to 3 groups        selected from a halogen atom, mono- or di-C₁ to C₆ alkylamino,        C₁ to C₆ alkoxy, mono- or di-C₁ to C₆ alkylcarbamoyl, mono- or        di-C₇ to C₁₆ aralkylcarbamoyl, mono- or di-C₁ to C₁₀        heteroaryl-C₁ to C₆ alkylcarbamoyl, carboxyl, and C₁ to C₆        alkoxycarbonyl, (x) C₁ to C₅ alkylenedioxy, (xi) C₁ to C₆        alkylthio which may optionally be substituted with 1 to 3 groups        selected from a halogen atom, mono- or di-C₁ to C₆ alkylamino,        C₁ to C₆ alkoxy, mono- or di-C₁ to C₆ alkylcarbamoyl, mono- or        di-C₇ to C₁₆ aralkylcarbamoyl, mono- or di-C₁ to C₁₀        heteroaryl-C₁ to C₆ alkylcarbamoyl, carboxyl, and C₁ to C₆        alkoxy-carbonyl, (xii) amino, (xiii) mono-C₁ to C₆        alkylamino, (xiv) di-C₁ to C₆ alkylamino, (xv) 5- to 6-membered        cyclic amino, (xvi) C₁ to C₆ alkylcarbonyl, (xvii)        carboxyl, (xviii) C₁ to C₆ alkoxycarbonyl, (xix) carbamoyl, (xx)        thiocarbamoyl, (xxi) mono-C₁ to C₆ alkylcarbamoyl, (xxii) di-C₁        to C₆ alkylcarbamoyl, (xxiii) 5- to 6-membered cyclic        aminocarbonyl, (xxiv) sulfo, (xxv) C₁ to C₆        alkylsulfonyl, (xxvi) C₁ to C₆ alkoxycarbonylamino, (xxvii) C₁        to C₆ alkylcarbonylamino, (xxviii) mono- or di-C₁ to C₆        alkylaminocarbonylamino, (xxix) aminosulfonyl, and (xxx) mono-        or di-C₁ to C₆ alkylaminosulfonyl,    -   W indicates (1) a hydrogen atom, (2) a C₆ to C₁₄ aromatic        hydrocarbon group, (3) a 5- to 8-membered aromatic heterocyclic        group including 1 to 4 hetero atoms selected from a nitrogen        atom, a sulfur atom, and an oxygen atom, other than a carbon        atom, (4) a bicyclic or tricyclic aromatic group formed by        condensation of the above aromatic heterocyclic group and a C₆        to C₁₄ aromatic hydrocarbon ring, (5) C₁ to C₆ alkyl, or (6) a        5- to 7-membered heterocycloalkyl group which may optionally be        substituted with 1 to 3 groups selected from oxo and phenyl,    -   wherein each of the groups (2) to (4) of the above W may        optionally be substituted with 1 to 5 groups selected from the        group consisting of (i) a halogen atom, (ii) nitro, (iii)        cyano, (iv) C₁ to C₆ alkyl which may optionally be substituted        with a halogen atom, amino, C₁ to C₆ alkoxycarbonyl, C₁ to C₆        alkoxycarbonylamino, and carboxyl, (v) C₂ to C₆ alkenyl which        may optionally be substituted with 1 to 3 halogen atoms, (vi) C₂        to C₆ alkynyl which may optionally be substituted with 1 to 3        halogen atoms, (vii) C₃ to C₆ cycloalkyl, (viii) hydroxyl, (ix)        C₁ to C₆ alkoxy which may optionally be substituted with 1 to 3        groups selected from a halogen atom, hydroxyl, C₁ to C₆ alkoxy,        amino, and mono- or di-C₁ to C₆ alkylamino, (x) C₁ to C₅        alkylenedioxy, (xi) C₁ to C₆ alkylthio which may optionally be        substituted with 1 to 3 groups selected from a halogen atom,        hydroxyl, C₁ to C₆ alkoxy, amino, and mono- or di-C₁ to C₆        alkylamino, (xii) amino, (xiii) mono-C₁ to C₆ alkylamino, (xiv)        di-C₁ to C₆ alkylamino, (xv) 5- to 6-membered cyclic        amino, (xvi) C₁ to C₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁        to C₆ alkoxycarbonyl which may optionally be substituted with a        halogen atom, (xix) C₇ to C₁₆ aralkyloxycarbonyl which may        optionally be substituted with a halogen atom, (xx)        carbamoyl, (xxi) mono-C₁ to C₆ alkylcarbamoyl which may        optionally be substituted with 1 to 3 groups selected from a        halogen atom, hydroxyl, carboxyl, C₁ to C₆ alkoxy, amino, and        mono- or di-C₁ to C₆ alkylamino, (xxii) di-C₁ to C₆        alkylcarbamoyl which may optionally be substituted with        hydroxyl, (xxiii) 5- to 6-membered cyclic aminocarbonyl which        may optionally be substituted with C₁ to C₆        alkoxycarbonyl, (xxiv) C₆ to C₁₀ arylcarbamoyl, (xxv) C₁ to C₁₀        heteroarylcarbamoyl, (xxvi) C₇ to C₁₆ aralkylcarbamoyl, (xxvii)        C₁ to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl, (xxviii) N—C₁ to        C₆ alkyl-N—C₆ to C₁₂ arylcarbamoyl, (xxix) C₃ to C₆        cycloalkylcarbamoyl, (xxx) sulfo, (xxxi) C₁ to C₆        alkylsulfonyl, (xxxii) C₁ to C₆ alkylsulfonylamino, (xxxiii) C₆        to C₁₂ arylsulfonylamino which may optionally be substituted        with C₁ to C₆ alkyl, (xxxiv) C₁ to C₁₀        heteroarylsulfonylamino, (xxxv) C₁ to C₆        alkoxycarbonylamino, (xxxvi) C₁ to C₆        alkylcarbonylamino, (xxxvii) mono- or di-C₁ to C₆        alkylaminocarbonylamino, (xxxviii) C₆ to C₁₂ aryl, (xxxix) C₁ to        C₁₀ heteroaryl, (xl) C₆ to C₁₀ aryloxy, (xli) C₁ to C₁₀        heteroaryloxy, (xlii) C₇ to C₁₆ aralkyloxy, (xliii) C₁ to C₁₀        heteroaryl-C₁ to C₆ alkyloxy, (xliv) aminosulfonyl, (xlv) mono-        or di-C₁ to C₆ alkylaminosulfonyl, (xlvi) C₇ to C₁₆        aralkyloxycarbamoyl, and (xlvii) C₁ to C₁₀ heteroaryl-C₁ to C₆        alkyloxycarbamoyl,    -   X indicates (1) a bond, (2) linear or branched C₁ to C₆        alkylene, (3) an oxygen atom, (4) NR¹³, wherein R¹³ indicates a        hydrogen atom or a C₁ to C₆ alkyl group, or (5) —S(O)_(m)—        [where, m indicates an integer of 0 to 2],    -   Y indicates (1) —S(O)_(n)—, wherein n indicates an integer of 1        or 2, (2) —S(O)_(n)NH—, wherein n indicates an integer of 1 or        2], (3) —C(═O)—, (4) —C(═O)NH—, or (5) —C(═O)NR¹⁴—, wherein R¹⁴        indicates a C₁ to C₆ alkyl group,    -   Z indicates (1) a bond or (2) CR⁷R⁸, wherein R⁷ and R⁸ are,        independently,    -   (A) a hydrogen atom,    -   (B) C₁ to C₆ alkyl which may be substituted with 1 to 5 groups        selected from the group consisting of (i) carboxyl, (ii) C₁ to        C₆ alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl, (v) C₁ to C₆        alkoxy, and (vi) a halogen atom,    -   (C) C₆ to C₁₂ aryl or C₁ to C₁₀ heteroaryl which may optionally        be substituted with 1 to 5 groups selected from the group        consisting of (i) a halogen atom and (ii) an alkyl group which        may optionally be substituted with 1 to 3 halogen atoms,    -   (D) C₃ to C₆ cycloalkyl which may optionally be substituted with        1 to 5 groups selected from (i) a halogen atom and (ii) an alkyl        group which may optionally be substituted with 1 to 3 halogen        atoms,    -   (E) —COOR⁹ wherein R⁹ indicates a hydrogen atom or C₁ to C₆        alkyl, or    -   (F) CONR¹⁰R¹¹ wherein R¹⁰ and R¹¹ are independently,        -   (a) hydrogen atom,        -   (b) C₁ to C₆ alkyl which may optionally be substituted with            1 to 3 groups selected from the group consisting of (i) a            halogen atom, (ii) C₃ to C₆ cycloalkyl, (iii) carboxyl, (iv)            C₁ to C₆ alkoxycarbonyl, (v) C₁ to C₆ alkylcarbonyl, (vi)            carbamoyl, (vii) mono-C₁ to C₆ alkylcarbamoyl, (viii) di-C₁            to C₆ alkylcarbamoyl, (ix) C₆ to C₁₂ aryl, and (x) C₁ to C₁₀            heteroaryl,        -   (c) OR¹² wherein R¹² indicates a hydrogen atom or C₁ to C₆            alkyl, or        -   (d) (1) a C₆ to C₁₄ aromatic hydrocarbon group, (2) a 5- to            8-membered aromatic heterocyclic group including 1 to 4            hetero atoms selected from a nitrogen atom, a sulfur atom,            and an oxygen atom, other than a carbon atom, or (3) a            bicyclic or tricyclic aromatic group formed by condensation            of the above aromatic heterocyclic group and a C₆ to C₁₄            aromatic hydrocarbon ring,        -   wherein each of the groups (1) to (3) may be optionally            substituted with 1 to 5 groups selected from the group            consisting of (i) a halogen atom, (ii) nitro, (iii)            cyano, (iv) C₁ to C₆ alkyl which may optionally be            substituted with 1 to 3 halogen atoms, (v) C₂ to C₆ alkenyl            which may optionally be substituted with 1 to 3 halogen            atoms, (vi) C₂ to C₆ alkynyl which may optionally be            substituted with 1 to 3 halogen atoms, (vii) C₃ to C₆            cycloalkyl, (viii) hydroxyl, (ix) C₁ to C₆ alkoxy which may            optionally be substituted with 1 to 3 halogen atoms, (x) C₁            to C₅ alkylenedioxy, (xi) C₁ to C₆ alkylthio which may            optionally be substituted with 1 to 3 halogen atoms, (xii)            amino, (xiii) mono-C₁ to C₆ alkylamino, (xiv) di-C₁ to C₆            alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C₁ to            C₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁ to C₆            alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi)            mono-C₁ to C₆ alkylcarbamoyl, (xxii) di-C₁ to C₆            alkylcarbamoyl, (xxiii) C₆ to C₁₀ arylcarbamoyl, (xxiv) C₁            to C₁₀ heteroarylcarbamoyl, (xxv) sulfo, (xxvi) C₁ to C₆            alkylsulfonyl, (xxvii) aminosulfonyl, and (xxviii) mono- or            di-C₁ to C₆ alkylaminosulfonyl,    -   R¹ indicates (1) a hydrogen atom, (2) a halogen atom, or (3) C₁        to C₆ alkyl, or R¹ forms —CH═ together with X,    -   R² and R³ are independently (1) a hydrogen atom, (2) a halogen        atom, or (3) C₁ to C₆ alkyl,    -   R⁵ and R⁶ are independently (1) a hydrogen atom or (2) C₁ to C₆        alkyl which may optionally be substituted with a group selected        from the group consisting of i) carboxyl, (ii) C₁ to C₆        alkoxy, (iii) C₁ to C₆ alkoxycarbonyl, (iv) C₆ to C₁₂        aryloxycarbonyl, (v) C₁ to C₁₀ heteroaryloxycarbonyl, and (vi)        amino,    -   R² and R³ and also R⁵ and R⁶ may independently form a 3- to        8-membered ring, and    -   R⁴ indicates a (1) a hydrogen atom, (2) C₁ to C₆ alkylcarbamoyl,        or (3) C₁ to C₆ alkyl which may optionally be substituted with 1        to 3 groups selected from the group consisting of (i)        carbamoyl, (ii) mono- or di-C₁ to C₆ alkylcarbamoyl, (iii) mono-        or di-C₆ to C₁₂ arylcarbamoyl, (iv) mono- or di-C₁ to C₁₀        heteroarylcarbamoyl, (v) N—C₁ to C₆ alkyl-N—C₆ to C₁₂        arylcarbamoyl, (vi) N—C₁ to C₆ alkyl-N—C₁ to C₁₀        heteroarylcarbamoyl, (vii) mono- or di-C₇ to C₁₆        aralkylcarbamoyl, (viii) mono- or di-C₁ to C₁₀ heteroaryl-C₁ to        C₆ alkylcarbamoyl, (ix) carboxyl, and (x) C₁ to C₆        alkoxycarbonyl,    -   or its salt or solvate thereof.

Further, the present invention provides a pharmaceutical compositioncomprising the compound having the formula (I), or its pharmaceuticallyacceptable salt, or solvate thereof as the active ingredient, and achymase inhibitor comprising the compound having the formula (I).

Further, the present invention provides a method of production of thecompound having the formula (I), or its salt, or solvate thereof.Specifically, it provides the following methods:

[Method of Production (A)]

A method for producing the compound having formula (I), or its salt, orsolvate thereof, comprising a cyclization reaction of a compound havingthe formula (II):

wherein Ar, W, X, Y, Z, R¹, R², R³, R⁴, R⁵, and R⁶ are the same asdefined in the above formula (I),

-   -   Q¹ indicates a halogen atom, a C₆ to C₁₀ arylsulfonyloxy group        which may optionally be substituted with 1 to 3 halogen atoms,        or C₁ to C₄ alkylsulfonyloxy group which may optionally be        substituted with 1 to 3 halogen atoms

[Method of Production (B)]

A method for producing a compound, or its salt or a solvate thereofhaving the formula (I), wherein Y is —S(O)_(n)NH— (wherein n indicatesan integer of 1 or 2) or —C(═O)NH—, comprising the coupling reaction ofthe compound, or a salt thereof, having the formula (III):

wherein Ar, X, R¹, R², R³, R⁵, and R⁶ are the same as defined in theabove formula (I), and

-   -   P indicates a protective group selected from the group        consisting of (1) allyl, (2) allyloxycarbonyl, (3)        9-fluorenylmethylcarbonyl, (4) linear or branched C₁ to C₆        alkyloxycarbonyl which may optionally be substituted with 1 to 3        halogen atoms, (5) linear or branched C₁ to C₆ alkylcarbonyl        which may optionally be substituted with 1 to 3 halogen        atoms, (6) C₇ to C₁₆ aralkyl which may optionally be substituted        with 1 to 3 groups selected from (i) a halogen atom, (ii) C₁ to        C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv) nitro, (7) C₅ to C₁₆        arylcarbonyl which may optionally be substituted with 1 to 3        groups selected from (i) a halogen atom, (ii) C₁ to C₆        alkyl, (iii) C₁ to C₆ alkoxy, and (iv) nitro, (8) C₇ to C₁₆        aralkyloxycarbonyl which may be substituted with 1 to 3 groups        selected from (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁        to C₆ alkoxy, and (iv) nitro, or (9) C₅ to C₁₆ arylsulfonyl        which may optionally be substituted with 1 to 3 groups selected        from (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆        alkoxyl, and (iv) nitro, or R⁴, wherein R⁴ is the same as        defined in the above formula (I), the compound (IV), or a salt        thereof, having the formula (IV):

wherein Q² and Q³ indicate, independently, nitro, C₆ to C₁₀ aryloxygroup which may optionally be substituted with 1 to 3 halogen atoms, ora halogen atom, and Y′ indicates —S(O)_(n)— (wherein n indicates aninteger of 1 or 2) or C(═O),and the compound (V), or a salt thereof, having the formula (V):

wherein W and Z are the same as defined as in the above formula (I), andthe optional deprotection reaction of the coupling product describedabove.

Further, as another aspect of the present invention, there is providedthe compound, or its salt, or a solvate thereof, having the formula(Va), which is useful as starting materials to produce the compoundhaving the formula (I):

wherein W′ indicates (1) a 6-membered aromatic hydrocarbon group or (2)a 6-membered aromatic heterocyclic group having 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom, and an oxygen atom, otherthan a carbon atom,

-   -   wherein the groups (1) and (2) of W′ may optionally be        substituted with 1 to 4 groups selected from the group        consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv)        C₁ to C₆ alkyl which may optionally be substituted with 1 to 3        groups selected from a halogen atom, amino, C₁ to C₆        alkoxycarbonyl, C₁ to C₆ alkoxycarbonylamino, and carboxyl, (v)        C₂ to C₆ alkenyl which may optionally be substituted with 1 to 3        halogen atoms, (vi) C₂ to C₆ alkynyl which may optionally be        substituted with 1 to 3 halogen atoms, (vii) C₃ to C₆        cycloalkyl, (viii) hydroxyl, (ix) C₁ to C₆ alkoxy which may        optionally be substituted with 1 to 3 groups selected from a        halogen atom, hydroxyl, C₁ to C₆ alkoxy, amino, and mono- or        di-C₁ to C₆ alkylamino, (x) C₁ to C₅ alkylenedioxy, (xi) C₁ to        C₆ alkylthio which may optionally be substituted with 1 to 3        groups selected from a halogen atom, hydroxyl, C₁ to C₆ alkoxy,        amino, and mono- or di-C₁ to C₆ alkylamino, (xii) amino, (xiii)        mono-C₁ to C₆ alkylamino, (xiv) di-C₁ to C₆ alkylamino, (xv) 5-        to 6-membered cyclic amino, (xvi) C₁ to C₆ alkylcarbonyl, (xvii)        carboxyl, (xviii) C₁ to C₆ alkoxycarbonyl, (xix) C₇ to C₁₆        aralkyloxycarbonyl, (xx) carbamoyl, (xxi) mono-C₁ to C₆        alkylcarbamoyl which may optionally be substituted with 1 to 3        groups selected from a halogen atom, hydroxyl, carboxyl, C₁ to        C₆ alkoxy, amino, and mono- or di-C₁ to C₆ alkylamino, (xxii)        di-C₁ to C₆ alkylcarbamoyl which may optionally be substituted        with hydroxyl, (xxiii) 5- to 6-membered cyclic aminocarbonyl        which may optionally be substituted with C₁ to C₆        alkoxycarbonyl, (xxiv) C₆ to C₁₀ arylcarbamoyl, (xxv) C₁ to C₁₀        heteroarylcarbamoyl, (xxvi) C₇ to C₁₆ aralkylcarbamoyl, (xxvii)        C₁ to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl, (xxxiii) N—C₁ to        C₆ alkyl-N—C₆ to C₁₂ arylcarbamoyl, (xxix) C₃ to C₆        cycloalkylcarbamoyl, (xxx) sulfo, (xxxi) C₁ to C₆        alkylsulfonyl, (xxxii) C₁ to C₆ alkylsulfonylamino, (xxxiii) C₆        to C₁₂ arylsulfonylamino which may be substituted with C₁ to C₆        alkyl, (xxxiv) C₁ to C₁₀ heteroarylsulfonylamino, (xxxv) C₁ to        C₆ alkoxycarbonylamino, (xxxvi) C₁ to C₆        alkylcarbonylamino, (xxxvii) mono- or di-C₁ to C₆        alkylaminocarbonylamino, (xxxviii) C₆ to C₁₂ aryl, (xxxix) C₁ to        C₁₀ heteroaryl, (xl) C₆ to C₁₀ aryloxy, (xli) C₁ to C₁₀        heteroaryloxy, (xlii) C₇ to C₁₆ aralkyloxy, (xliii) C₁ to C₁₀        heteroaryl-C₁ to C₆ alkyloxy, (xliv) aminosulfonyl, (xlv) mono-        or di-C₁ to C₆ alkylaminosulfonyl, (xlvi) C₇ to C₁₆        aralkyloxycarbamoyl, and (xlvii) C₁ to C₁₀ heteroaryl-C₁ to C₆        alkyloxycarbamoyl,    -   R¹⁸ indicates a C₂ to C₄ alkyl group which may optionally be        substituted with 1 to 3 halogen atoms, and R¹⁹ indicates a        hydrogen atom, C₁ to C₆ alkyl group which may optionally be        substituted with 1 to 0.3 halogen atoms, or C₇ to C₁₆ aralkyl        group which may optionally be substituted with 1 to 3 halogen        atoms.

Among the compounds having the formula (Va), when W′ indicates phenyland the NH₂—CH(R¹⁸)— group and R¹⁹O—C(═O)— group are 1,4 substituted, W′is preferably substituted with 1 to 4 groups selected from the groupconsisting of (ii) nitro, (iv) C₁ to C₆ alkyl substituted with 1 to 3groups selected from amino, C₁ to C₆ alkoxycarbonyl, C₁ to C₆alkoxycarbonylamino, and carboxyl, (v) C₂ to C₆ alkenyl which mayoptionally be substituted with 1 to 3 halogen atoms, (vi) C₂ to C₆alkynyl which may optionally be substituted with 1 to 3 halogen atoms,(vii) C₃ to C₆ cycloalkyl, (viii) hydroxyl, (ix) C₁ to C₆ alkoxysubstituted with 1 to 3 groups selected from hydroxyl, C₁ to C₆ alkoxy,amino, and mono- or di-C₁ to C₆ alkylamino, (x) C₁ to C₅ alkylenedioxy,(xi) C₁ to C₆ alkylthio which may optionally be substituted with 1 to 3groups selected from a halogen atom, hydroxyl, C₁ to C₆ alkoxy, amino,and mono- or di-C₁ to C₆ alkylamino, (xii) amino, (xiii) mono-C₁ to C₆alkylamino, (xiv) di-C₁ to C₆ alkylamino, (xv) 5- to 6-membered cyclicamino, (xvi) C₁ to C₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁ to C₆alkoxycarbonyl, (xix) C₇ to C₁₆ aralkyloxycarbonyl, (xx) carbamoyl,(xxi) mono-C₁ to C₆ alkylcarbamoyl which may optionally be substitutedwith 1 to 3 groups selected from a halogen atom, hydroxyl, carboxyl, C₁to C₆ alkoxy, amino, and mono- or di-C₁ to C₆ alkylamino, (xxii) di-C₁to C₆ alkylcarbamoyl which may optionally be substituted with hydroxyl,(xxiii) 5- to 6-membered cyclic aminocarbonyl which may optionally besubstituted with C₁ to C₆ alkoxycarbonyl, (xxiv) C₆ to C₁₀arylcarbamoyl, (xxv) C₁ to C₁₀ heteroarylcarbamoyl, (xxvi) C₇ to C₁₆aralkylcarbamoyl, (xxvii) C₁ to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl,(xxviii) N—C₁ to C₆ alkyl-N—C₆ to C₁₂ arylcarbamoyl, (xxix) C₃ to C₆cycloalkylcarbamoyl, (xxx) sulfo, (xxxi) C₁ to C₆ alkylsulfonyl, (xxxii)C₁ to C₆ alkylsulfonylamino, (xxxiii) C₆ to C₁₂ arylsulfonylamino whichmay optionally be substituted with C₁ to C₆ alkyl, (xxxiv) C₁ to C₆heteroarylsulfonylamino, (xxxv) C₁ to C₆ alkoxycarbonylamino, (xxxvi) C₁to C₆ alkylcarbonylamino, (xxxvii) mono- or di-C₁ to C₆alkylaminocarbonylamino, (xxxviii) C₆ to C₁₂ aryl, (xxxix) C₁ to C₁₀heteroaryl, (xl) C₆ to C₁₀ aryloxy, (xli) C₁ to C₁₀ heteroaryloxy,(xlii) C₇ to C₁₆ aralkyloxy, (xliii) C₁ to C₁₀ heteroaryl-C₁ to C₆alkyloxy, (xliv) aminosulfonyl, (xlv) mono- or di-C₁ to C₆alkylaminosulfonyl, (xlvi) C₇ to C₁₆ aralkyloxycarbamoyl, and (xlvii) C₁to C₁₀ heteroaryl-C₁ to C₆ alkyloxycarbamoyl. More preferably, W′ may besubstituted with (ii) nitro, (viii) hydroxyl, and (xii) amino.

Further, as another aspect of the present invention, there is provided acompound, or its salt or a solvate thereof, having of the formula (VIa),which is useful as starting materials to produce the compound having theformula (I):

wherein R¹, R², and R³ are the same as defined in the above formula (I),P is the same as defined in the above formula (III),

-   -   X′ indicates methylene, or X′ forms —CH═ together with R¹,    -   P′ indicates a protective group selected from the group        consisting of (1) allyl, (2) allyloxycarbonyl, (3)        9-fluorenylmethylcarbonyl, (4) linear or branched C₁ to C₆        alkyloxycarbonyl which may optionally be substituted with 1 to 3        halogen atoms, (5) linear or branched C₁ to C₆ alkylcarbonyl        which may optionally be substituted with 1 to 3 halogen        atoms, (6) C₇ to C₁₆ aralkyl which may optionally be substituted        with 1 to 3 of (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁        to C₆ alkoxy, or (iv) nitro, (7) C₅ to C₁₆ arylcarbonyl which        may optionally be substituted with 1 to 3 of (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv)        nitro, (8) C₇ to C₁₆ aralkyloxycarbonyl which may optionally be        substituted with 1 to 3 of (i) a halogen atom, (ii) C₁ to C₆        alkyl, (iii) C₁ to C₆ alkoxy, or (iv) nitro, and (9) C₅ to C₁₆        arylsulfonyl which may optionally be substituted with 1 to 3        of (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆        alkoxy, or (iv) nitro, or a hydrogen atom,    -   R²⁰ is (1) a halogen atom, (2) nitro, (3) cyano, (4) C₁ to C₆        alkyl which may optionally be substituted with 1 to 3 halogen        atoms, (5) hydroxyl, or (6) C₁ to C₆ alkoxy which may be        substituted with 1 to 3 groups selected from a halogen atom, C₁        to C₆ alkoxy, carboxyl, and C₁ to C₆ alkoxycarbonyl,    -   R²¹, R²², R²³, and R²⁴ are, independently, (1) a halogen        atom, (2) nitro, (3) cyano, (4) C₁ to C₆ alkyl which may be        substituted with 1 to 3 halogen atoms, (5) hydroxyl, or (6) C₁        to C₆ alkoxy which may optionally be substituted with 1 to 3        groups selected from a halogen atom, C₁ to C₆ alkoxy, carboxyl,        and C₁ to C₆ alkoxycarbonyl, or a hydrogen atom,        provided that the following compounds are excluded:        (1) Compounds where R²⁰ and R²⁴ are chlorine atoms and R²¹, R²²,        and R²³ are hydrogen atoms,        (2) Compounds where R²⁰, R²², and R²⁴ are methyl and R²¹ and R²³        are hydrogen atoms, and        (3) Compounds where R²⁰ is a chlorine atom or bromine atom and        R²¹, R²², R²³, and R²⁴ are hydrogen atoms.

When the compounds, or a salt thereof, having the formulae (I), (II),(III), (V), (Va), and (VIa) have asymmetric carbon atoms in theirstructures, their optically active compounds and their mixtures are alsoincluded in the scope of the present invention. When they have two ormore asymmetric carbon atoms, the diastereomer mixtures are alsoincluded in the scope of the present invention. Further, when thecompounds, or a salt thereof, having the formulae (I), (II), (III), (V),(Va), and (VIa) have double bonds in their structures, all of thecis-forms, trans-forms, and their mixtures are also included in thescope of the present invention.

Further, the compounds having the formula (I) or a salt thereof, may bebrought into contact with, or recrystallized from the solvent such aswater, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,2-methyl-1-propanol, 1-pentanol, 3-methyl-1-butanol, 2-methoxyethanol,2-ethoxyethanol, formic acid, ethyl formate, acetic acid, methylacetate, ethyl acetate, propyl acetate, isobutyl acetate, acetone,methylethylketone, methylisobutylketone (preferably, water, ethanol,1-propanol, 2-propanol, 1-butanol, acetic acid, ethyl acetate, acetone,etc.), or other solvents, or mixed solvents including the same so as toform their solvates. These solvates are also included in the scope ofthe present invention.

The compounds having the formula (I), or its salt, or a solvate thereof,of the present invention have a chymase inhibitory activity and areuseful as a pharmaceutical for the prevention or treatment of bronchialasthma, urticaria, atopic dermatitis, allergic conjunctivitis, rhinitis,rheumatoid arthritis, mastocytosis, scleroderma, heart failure, cardiachypertrophy, congestive heart failure, hypertension, atherosclerosis,myocardial ischemia, myocardial infarction, restenosis after PTCA,restenosis after bypass graft surgery, ischemic peripheral circulatorydisorders, hyperaldosteronism, diabetic retinopathy, diabeticnephropathy, nephritis, glomerulosclerosis, renal insufficiency,psoriasis, solid tumor, postoperative adhesion, glaucoma, and ocularhypertension, and other diseases.

Further, the production method of the present invention provides apractical production method of 1,4-diazepan-2,5-dione derivative havingan electronic withdrawing group at its 4-position nitrogen atom, whichare not reported hereinbefore.

BEST MODE FOR CARRYING OUT THE INVENTION

In the description, the terms “alkyl”, “alkenyl”, “alkynyl”, “alkoxy”,and “alkylene” include both linear and branched forms.

[1. Explanation of Compounds Having Formula (I)]

In the above-mentioned formula (I), as examples of the “C₆ to C₁₄aromatic hydrocarbon group” expressed by Ar, a monocyclic or polycyclicaromatic hydrocarbon group, more specifically, phenyl, biphenyl,naphthyl, indenyl, anthryl, phenanthryl (preferably, phenyl, biphenyl,naphthyl, etc., particularly preferably phenyl etc.), or other 6- to14-membered monocyclic or polycyclic aromatic hydrocarbon group etc. maybe mentioned.

Further, as examples of the “5- to 8-membered aromatic heterocyclicgroup including 1 to 4 hetero atoms selected from a nitrogen atom,sulfur atom, and oxygen atom, other than a carbon atom” expressed by Ar,for example a monocyclic group including 1 or more (for example, 1 to 4,preferably 1 to 3) hetero atoms which consist of 1 or 2 species ofhetero atoms selected from a nitrogen atom, oxygen atom, and sulfuratom, other than a carbon atom, or its condensed aromatic heterocyclicgroup, more specifically, thienyl, furyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyridyl, pyradinyl, pyrimidinyl, pyridazinyl,naphthylidinyl, purinyl, and other aromatic heterocyclic groups(preferably pyridyl, thienyl, and furyl) etc. may be mentioned.

Further, as examples of the “bicyclic or tricyclic aromatic group formedby condensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon ring” expressed by Ar, benzothienyl, benzofuryl,indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,benzodioxolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl(preferably, benzothienyl, benzofuryl, benzodioxolyl, and quinolyl),etc. may be mentioned.

Among these, as examples of the above-mentioned (1) aromatic hydrocarbongroup, (2) aromatic heterocyclic group, or (3) bicyclic or tricyclicaromatic group formed by condensation of the above aromatic heterocyclicgroup and a C₆ to C₁₄ aromatic hydrocarbon group, expressed by Ar,phenyl and naphthyl are particularly preferred.

Next, the substituent groups (i) to (xxx) of the groups expressed by Arin the above-mentioned formula (I) are shown together with specificexamples:

(i) a halogen atom (for example, fluorine, chlorine, bromine, and iodinemay be mentioned)(ii) nitro(iii) cyano(iv) C₁ to C₆ alkyl which may optionally be substituted with 1 to 3halogen atoms (as the halogen atom, fluorine, chlorine, bromine, andiodine may be mentioned, and as the C₁ to C₆ alkyl, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,n-hexyl, etc. may be mentioned. As specific examples, methyl,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, n-propyl,i-propyl, n-butyl, butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc.(preferably methyl, ethyl, trifluoromethyl, etc.) may be mentioned),(v) C₂ to C₆ alkenyl which may optionally be substituted with 1 to 3halogen atoms (as the halogen atom, fluorine, chlorine, bromine, andiodine may be mentioned, and as the C₂ to C₆ alkenyl, for example,vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl,etc. may be mentioned)(vi) C₂ to C₆ alkynyl which may optionally be substituted with 1 to 3halogen atoms (as the halogen atom, fluorine, chlorine, bromine, andiodine may be mentioned, and as the C₂ to C₆ alkynyl, for example,2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc. may be mentioned),(vii) C₃ to C₆ cycloalkyl (for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc. may be mentioned)(viii) hydroxyl(ix) C₁ to C₆ alkoxy which may optionally be substituted with 1 to 3groups selected from a halogen atom, mono- or di-C₁ to C₆ alkylamino, C₁to C₆ alkoxy, mono- or di-C₁ to C₆ alkylcarbamoyl, mono- or di-C₇ to C₁₆aralkylcarbamoyl, mono- or di-C₁ to C₁₀ heteroaryl-C₁ to C₆alkylcarbamoyl, carboxyl, and C₁ to C₆ alkoxycarbonyl (as the C₁ to C₆alkoxy, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, etc. may bementioned. As the substituent of alkoxy group, fluorine, chlorine,bromine, iodine, methylamino, dimethylamino, methoxy, ethoxy,N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-benzylcarbamoyl,N-(2-picolyl)carbamoyl, methoxycarbonyl, t-butoxycarbonyl, carboxyl,etc. may be mentioned. As specific examples, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyloxy,trichloromethyloxy, methoxymethyloxy, ethoxymethyloxy,N-methyl-carbamoylmethyloxy, N,N-dimethylcarbamoylmethyloxy,N-benzylcarbamoylmethyloxy, N-(2-picolyl)-carbamoylmethyloxy,methoxycarbonylmethyloxy, t-butoxycarbonylmethyloxy, carboxylmethyloxy,etc. (preferably methoxy, ethoxy, N-methylcarbamoylmethyloxy,N-benzylcarbamoylmethyloxy, N-(2-picolyl)-carbamoylmethyloxy,methoxycarbonylmethyloxy, t-butoxycarbonylmethyloxy, andcarboxylmethyloxy) may be mentioned)(x) C₁ to C₅ alkylenedioxy (for example methylenedioxy, ethylenedioxy,etc. may be mentioned),(xi) C₁ to C₆ alkylthio which may optionally be substituted with 1 to 3groups selected from a halogen atom, mono- or di-C₁ to C₆ alkylamino, C₁to C₆ alkoxy, mono- or di-C₁ to C₆ alkylcarbamoyl, mono- or di-C₇ to C₁₆aralkylcarbamoyl, mono- or di-C₁ to C₁₀ heteroaryl-C₁ to C₆alkylcarbamoyl, carboxyl, and C₁ to C₆ alkoxycarbonyl (as the C₁ to C₆alkylthio, for example methylthio, ethylthio, n-propylthio,i-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio,n-pentylthio, n-hexylthio, etc. may be mentioned, as examples ofsubstituent groups of C₁ to C₆ alkylthio, fluorine, chlorine, bromine,iodine, methylamino, dimethylamino, methoxy, ethoxy, N-methylcarbamoyl,N,N-dimethylcarbamoyl, N-benzylcarbamoyl, N-(2-picolyl)-carbamoyl,methoxycarbonyl, t-butoxycarbonyl, carboxyl, etc. may be mentioned. Asspecific examples, methylthio, ethylthio, n-propylthio, i-propylthio,n-butylthio, i-butylthio, t-butylthio, trifluoromethylthio,trichloromethylthio, methoxymethylthio, ethoxymethylthio,N-methylcarbamoylmethylthio, N-benzylcarbamoylmethylthio,N-(2-picolyl)-carbamoylmethylthio, methoxycarbonylmethylthio,t-butoxycarbonylmethylthio, carboxylmethylthio, etc. may be mentioned)(xii) amino(xiii) mono-C₁ to C₆ alkylamino (for example, N-methylamino etc. may bementioned)(xiv) di-C₁ to C₆ alkylamino (for example, N,N-dimethylamino etc. may bementioned)(xv) 5- to 6-membered cyclic amino (for example, morpholino, piperidino,piperazino, etc. may be mentioned)(xvi) C₁ to C₆ alkylcarbonyl (for example, acetyl, propanoyl, butyryl,isobutyryl, pivaroyl, etc. may be mentioned)(xvii) carboxyl(xviii) C₁ to C₆ alkoxycarbonyl (for example methoxycarbonyl,ethoxycarbonyl, etc. may be mentioned)(xix) carbamoyl(xx) thiocarbamoyl(xxi) mono-C₁ to C₆ alkylcarbamoyl (for example, N-methylcarbamoyl,N-ethylcarbamoyl, etc. may be mentioned)(xxii) di-C₁ to C₆ alkylcarbamoyl (for example, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, etc. may be mentioned)(xxiii) 5- to 6-membered cyclic aminocarbonyl (for example,morpholinocarbonyl, piperidinocarbonyl, piperadinocarbonyl, etc. may bementioned)(xxiv) sulfo(xxv) C₁ to C₆ alkylsulfonyl (for example, methanesulfonyl etc. may bementioned)(xxvi) C₁ to C₆ alkoxycarbonylamino (for example, methoxycarbonylamino,ethoxycarbonylamino, etc. may be mentioned)(xxvii) C₁ to C₆ alkylcarbonylamino (for example, acetoamide group etc.may be mentioned)(xxviii) mono- or di-C₁ to C₆ alkylaminocarbonylamino (for example,N-methylaminocarbonylamino etc. may be mentioned)(xxix) aminosulfonyl and(xxx) mono- or di-C₁ to C₆ alkylaminosulfonyl (for example,methylaminosulfonyl etc. may be mentioned).

Among the substituent groups of the groups expressed by above-mentionedAr, (i) a halogen atom, (iv) C₁ to C₆ alkyl which may be substitutedwith 1 to 3 halogen atoms, and (ix) C₁ to C₆ alkoxy which may optionallybe substituted with 1 to 3 groups selected from a halogen atom, mono- ordi-C₁ to C₆ alkylamino, C₁ to C₆ alkoxy, mono- or di-C₁ to C₆alkylcarbamoyl, mono- or di-C₇ to C₁₆ aralkylcarbamoyl, mono- or di-C₁to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl, carboxyl, and C₁ to C₆alkoxycarbonyl are particularly preferable.

As examples of the “C₆ to C₁₄ aromatic hydrocarbon group”, “5- to8-membered aromatic heterocyclic group including 1 to 4 hetero atomsselected from a nitrogen atom, sulfur atom, and oxygen atom other than acarbon atom”, and “bicyclic or tricyclic aromatic group formed bycondensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon group” expressed by W, ones the same as theexamples of the “C₆ to C₁₄ aromatic hydrocarbon group”, “5- to8-membered aromatic heterocyclic group including 1 to 4 hetero atomsselected from a nitrogen atom, sulfur atom, and oxygen atom other than acarbon atom”, and “bicyclic or tricyclic aromatic group formed bycondensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon” expressed by the Ar may be mentioned.

As examples of the “C₆ to C₁₄ aromatic hydrocarbon group”, “5- to8-membered aromatic heterocyclic group including 1 to 4 hetero atomsselected from a nitrogen atom, sulfur atom, and oxygen atom, other thana carbon atom”, and “bicyclic or tricyclic aromatic group formed by thecondensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon group” expressed by W, phenyl, pyridyl, thienyl,and furyl are particularly preferred.

Next, the substituent groups (i) to (xlvii) of the “C₆ to C₁₄ aromatichydrocarbon group”, “5- to 8-membered aromatic heterocyclic groupincluding 1 to 4 hetero atoms selected from a nitrogen atom, sulfuratom, and oxygen atom, other than a carbon atom”, and “bicyclic ortricyclic aromatic group formed by the condensation of the abovearomatic heterocyclic group and a C₆ to C₁₄ aromatic hydrocarbon group”expressed by W in the above-mentioned formula (I) are shown togetherwith specific examples.

-   -   (i) a halogen atom (for example fluorine, chlorine, bromine,        iodine may be mentioned)    -   (ii) nitro    -   (iii) cyano    -   (iv) C₁ to C₆ alkyl which may optionally be substituted with 1        to 3 groups selected from a halogen atom, amino, C₁ to C₆        alkoxycarbonyl, C₁ to C₆ alkoxycarbonylamino, and carboxyl (as        C₁ to C₆ alkyl, methyl, ethyl, n-propyl, i-propyl, n-butyl,        i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc. may be        mentioned, and as a substituent group of C₁ to C₆ alkyl,        fluorine, chlorine, bromine, iodine, amino, methoxycarbonyl,        ethoxycarbonyl, methoxycarbonylamino, ethoxycarbonylamino,        t-butoxycarbonylamino, and carboxyl may be mentioned. As        specific examples, methyl, fluoromethyl, difluoromethyl,        trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,        carboxylmethyl, ethyl, 2,2,2-trifluoroethyl, aminoethyl,        methoxycarbonylethyl, t-butoxycarbonylaminoethyl, carboxylethyl,        n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,        n-pentyl, n-hexyl, etc. (preferably, methyl, ethyl,        trifluoromethyl, aminoethyl, carboxylmethyl, etc.) may be        mentioned)    -   (v) C₂ to C₆ alkenyl which may optionally be substituted with 1        to 3 halogen atoms (as a halogen atom, fluorine, chlorine,        bromine, and iodine may be mentioned, and as C₂ to C₆ alkenyl,        for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl,        4-pentene-1-yl, 5-hexen-1-yl, etc. may be mentioned)    -   (vi) C₂ to C₆ alkynyl which may optionally be substituted with 1        to 3 halogen atoms (as a halogen atom, fluorine, chlorine,        bromine, and iodine may be mentioned, as C₂ to C₆ alkynyl, for        example, 2-buten-1-yl, 4-pentyne-1-yl, 5-hexyne-1-yl, etc. may        be mentioned)    -   (vii) C₃ to C₆ cycloalkyl (for example, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, etc. may be mentioned.)    -   (viii) hydroxyl    -   (ix) C₁ to C₆ alkoxy which may optionally be substituted with 1        to 3 groups selected from a halogen atom, hydroxyl, C₁ to C₆        alkoxy, amino, and mono- or di-C₁ to C₆ alkylamino (as C₁ to C₆        alkoxy, for example, methoxy, ethoxy, n-propoxy, i-propoxy,        n-butoxy, butoxy, s-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy,        etc. may be mentioned. As a substituent group of alkoxy,        fluorine, chlorine, bromine, iodine, methylamino, dimethylamino,        methoxy, ethoxy, N-methylcarbamoyl, N,N-dimethylcarbamoyl,        N-benzylcarbamoyl, N-(2-picolyl)-carbamoyl, methoxycarbonyl,        t-butoxycarbonyl, carboxyl, etc. may be mentioned. As specific        examples, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,        i-butoxy, t-butoxy, trifluoromethyloxy, trichloromethyloxy,        methoxymethyloxy, ethoxymethyloxy, N-methyl-carbamoylmethyloxy,        N-benzylcarbamoylmethyloxy, N-(2-picolyl)-carbamoylmethyloxy,        methoxycarbonylmethyloxy, t-butoxycarbonylmethyloxy,        carboxylmethyloxy, etc. (preferably, methoxy, ethoxy,        N-methyl-carbamoylmethyloxy, N-benzylcarbamoylmethyloxy,        N-(2-picolyl)-carbamoylmethyloxy, methoxycarbonylmethyloxy,        t-butoxycarbonylmethyloxy, and carboxylmethyloxy) may be        mentioned)    -   (x) C₁ to C₅ alkylenedioxy (for example methylenedioxy,        ethylenedioxy, etc. may be mentioned)    -   (xi) C₁ to C₆ alkylthio which may optionally be substituted with        1 to 3 groups selected form a halogen atom, hydroxyl, C₁ to C₆        alkoxy, amino, and mono- or di-C₁ to C₆ alkylamino (as C₁ to C₆        alkylthio, for example, methylthio, ethylthio, n-propylthio,        i-propylthio, n-butylthio, i-butylthio, s-butylthio,        t-butylthio, n-pentylthio, n-hexylthio, etc. may be mentioned,        and as examples of substituent groups of C₁ to C₆ alkylthio,        fluorine, chlorine, bromine, iodine, methylamino, dimethylamino,        methoxy, ethoxy, N-methylcarbamoyl, N,N-dimethylcarbamoyl,        N-benzylcarbamoyl, N-(2-picolyl)-carbamoyl, methoxycarbonyl,        t-butoxycarbonyl, carboxyl, etc. may be mentioned. As specific        examples, methylthio, ethylthio, n-propylthio, i-propylthio,        n-butylthio, butylthio, t-butylthio, trifluoromethylthio,        trichloromethylthio, methoxymethylthio, ethoxymethylthio,        N-methylcarbamoylmethylthio, N-benzylcarbamoylmethylthio,        N-(2-picolyl)-carbamoylmethylthio, methoxycarbonylmethylthio,        t-butoxycarbonylmethylthio, carboxylmethylthio, etc. may be        mentioned)    -   (xii) amino    -   (xiii) mono-C₁ to C₆ alkylamino (for example, N-methylamino etc.        may be mentioned)    -   (xiv) di-C₁ to C₆ alkylamino (for example, N,N-dimethylamino        etc. may be mentioned)    -   (xv) 5- to 6-membered cyclic amino (for example morpholino,        piperidino, piperazino, etc. may be mentioned)    -   (xvi) C₁ to C₆ alkylcarbonyl (for example acetyl, propanoyl,        butyryl, isobutyryl, pivaloyl, etc. may be mentioned)    -   (xvii) carboxyl    -   (xviii) C₁ to C₆ alkoxycarbonyl which may optionally be        substituted with a halogen atom (for example, methoxycarbonyl,        ethoxycarbonyl, etc. may be mentioned)    -   (xix) C₇ to C₁₆ aralkyloxycarbonyl which may optionally be        substituted with a halogen atom (for example, benzyloxycarbonyl        etc. may be mentioned)    -   (xx) carbamoyl    -   (xxi) mono-C₁ to C₆ alkyl-carbamoyl which may optionally be        substituted with 1 to 3 groups selected from a halogen atom,        hydroxyl, carboxyl, C₁ to C₆ alkoxy, amino, and mono- or di-C₁        to C₆ alkylamino (as a mono-C₁ to C₆ alkylcarbamoyl, for        example, N-methylcarbamoyl, N-ethylcarbamoyl, etc. may be        mentioned, and as a substituent group of mono-C₁ to C₆        alkylcarbamoyl, fluorine, chlorine, bromine, iodine, hydroxyl,        carboxyl, methoxy, ethoxy, amino, N-methylamino,        N,N-dimethylamino, etc. may be mentioned)    -   (xxii) di-C₁ to C₆ alkylcarbamoyl which may optionally be        substituted with hydroxyl (for example, N,N-dimethylcarbamoyl,        N,N-diethylcarbamoyl, N-hydroxyethyl-N-methylcarbamoyl, etc. may        be mentioned)    -   (xxiii) 5- to 6-membered cyclic aminocarbonyl which may        optionally be substituted with C₁ to C₆ alkoxycarbonyl (for        example, morpholinocarbonyl, piperidinocarbonyl,        piperazinocarbonyl, t-butoxycarbonylpiperazinolcarbonyl, etc.        may be mentioned)    -   (xxiv) C₆-C₁₀ arylcarbamoyl (for example, phenylcarbamoyl etc.        may be mentioned)    -   (xxv) C₁ to C₁₀ heteroarylcarbamoyl (for example,        pyridylcarbamoyl etc. may be mentioned)    -   (xxvi) C₇ to C₁₆ aralkylcarbamoyl (for example,        benzylaminocarbonyl etc. may be mentioned)    -   (xxvii) C₁ to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl (for        example, pyridylmethylcarbamoyl, pyridylethylcarbamoyl, etc. may        be mentioned)    -   (xxviii) N—C₁ to C₆ alkyl-N—C₆ to C₁₂ aryl-carbamoyl (for        example, N-methyl-N-phenylcarbamoyl etc. may be mentioned)    -   (xxix) C₃ to C₆ cycloalkylcarbamoyl (for example,        cyclopropylcarbamoyl, cyclohexylcarbamoyl, etc. may be        mentioned)    -   (xxx) sulfo    -   (xxxi) C₁ to C₆ alkylsulfonyl (for example, methane sulfonyl        etc. may be mentioned)    -   (xxxii) C₁ to C₆ alkylsulfonylamino (for example, methane        sulfonylamino etc. may be mentioned)    -   (xxxiii) C₆ to C₁₂ arylsulfonylamino which may optionally be        substituted with C₁ to C₆ alkyl (for example,        benzenesulfonylamino, methylbenzenesulfonylamino, etc. may be        mentioned.)    -   (xxxiv) C₁ to C₁₀ heteroarylsulfonylamino (for example,        pyridylsulfonylamino etc. may be mentioned)    -   (xxxv) C₁ to C₆ alkoxycarbonylamino (for example,        methoxycarbonylamino, ethoxycarbonylamino,        t-butoxycarbonylamino, etc. may be mentioned)    -   (xxxvi) C₁ to C₆ alkylcarbonylamino (for example, acetoamide        etc. may be mentioned) (xxxvii) mono- or di-C₁ to C₆        alkylaminocarbonylamino (for example,        N-methylaminocarbonylamino, N-ethylaminocarbonylamino, etc. may        be mentioned)    -   (xxxviii) C₆ to C₁₂ aryl (for example, phenyl etc. may be        mentioned)    -   (xxxix) C₁ to C₁₀ heteroaryl (C₁ to C₁₀ heteroaryl including 1        to 4 hetero atoms selected from a nitrogen atom, sulfur atom,        and oxygen atom (for example, pyridyl, pyrazolyl, imidazolyl,        etc.) may be mentioned)    -   (xl) C₆ to C₁₀ aryloxy (for example, phenoxy etc. may be        mentioned)    -   (xli) C₁ to C₁₀ heteroaryloxy (C₁ to C₁₀ heteroaryloxy including        1 to 4 hetero atoms selected from a nitrogen atom, sulfur atom,        and oxygen atom (for example, pyridyloxy, pyrazolyloxy,        imidazolyloxy, etc.) may be mentioned)    -   (xlii) C₇ to C₁₆ aralkyloxy (for example, benzyloxy etc. may be        mentioned)    -   (xliii) C₁ to C₁₀ heteroaryl-C₁ to C₆ alkyloxy (C₁ to C₁₀        heteroaryl-C₁ to C₆ alkyloxy including 1 to 4 hetero atoms        selected from a nitrogen atom, sulfur atom, and oxygen atom (for        example, pyridylmethyloxy, pyrazolylmethyloxy,        imidazolylmethyloxy, etc.) may be mentioned)    -   (xliv) aminosulfonyl    -   (xlv) mono- or di-C₁ to C₆ alkylaminosulfonyl (for example,        N-methylaminosulfonyl etc. may be mentioned)    -   (xlvi) C₇ to C₁₆ aralkyloxy-carbamoyl (for example,        benzyloxycarbamoyl etc. may be mentioned)    -   (xlvii) C₁ to C₁₀ heteroaryl-C₁ to C₆ alkyloxy-carbamoyl (C₁ to        C₁₀ heteroaryl-C₁ to C₆ alkyloxycarbamoyl including 1 to 4        hetero atoms selected from a nitrogen atom, sulfur atom, and        oxygen atom (for example, pyridylmethyloxycarbamoyl,        pyrazolylmethyloxycarbamoyl, imidazolylmethyloxycarbamoyl, etc.)        may be mentioned)

As examples of the C₁ to C₆ alkyl expressed by W in the above-mentionedformula (I), methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, n-hexyl, etc. may be mentioned.

As examples of the heterocycloalkyl group of the 5- to 7-memberedheterocycloalkyl group which may optionally be substituted with 1 to 3groups selected from oxo and phenyl expressed by W in theabove-mentioned formula (I), pyrrolidine, imidazolidine, piperidine,piperazine, etc. may be mentioned.

In the above-mentioned formula (I), X indicates (1) a bond, (2) linearor branched C₁ to C₆ alkylene, (3) oxygen atom, (4) NR¹³, where, R¹³indicates a hydrogen atom or C₁ to C₆ alkyl group, or (5) —S(O)_(m)—,where m indicates an integer of 0 to 2.

As specific examples of the “linear or branched C₁ to C₆ alkylene”expressed by X, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene,etc. may be mentioned. Further, as specific examples of the “NR¹³, whereR¹³ indicates a hydrogen atom or C₁ to C₆ alkyl group” expressed by X,—NH—, —NMe-, —NEt-, —N^(n)Pr-, —N^(i)Pr-, etc. may be mentioned. As X, amethylene group is particularly preferable.

In the above-mentioned formula (I), Y indicates (1) —S(O)_(n)—, where nindicates an integer of 1 or 2, (2) —S(O)_(n)NH—, where n indicates aninteger of 1 or 2, (3) —C(═O)—, (4) —C(═O)NH—, or (5) —C(═O)NR¹⁴—, whereR¹⁴ indicates a C₁ to C₆ alkyl group. As specific examples of the“—C(═O)NR¹⁴—, where R¹⁴ indicates a C₁ to C₆ alkyl group” expressed byY, —C(═O)NMe-, —C(═O)NEt-, —C(═O)N^(n)Pr-, —C(═O)N^(i)Pr-, etc. may bementioned. As Y, —SO₂— and —C(═O)NH— are particularly preferable.

Next, in the above-mentioned formula (I), the (A) to (F), which the R⁷and R⁸ of “CR⁷R⁸” expressed by Z independently indicate, are shown belowalong with specific examples:

-   -   (A) a hydrogen atom    -   (B) C₁ to C₆ alkyl which may optionally be substituted with 1 to        5 groups selected from the group consisting of (i)        carboxyl, (ii) C₁ to C₆ alkoxycarbonyl, (iii) phenyl, (iv)        hydroxyl, (v) C₁ to C₆ alkoxy, and (vi) a halogen atom (as        examples of C₁ to C₆ alkyl, methyl, ethyl, n-propyl, i-propyl,        n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc. may        be mentioned. As examples of a substituent group of C₁ to C₆        alkyl, carboxyl, methoxycarbonyl, ethoxycarbonyl,        n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,        i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, phenyl,        hydroxyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,        i-butoxy, t-butoxy, fluorine, chlorine, bromine, iodine, etc.        may be mentioned)    -   (C) C₆ to C₁₂ aryl or C₁ to C₁₀ heteroaryl which may optionally        be substituted with 1 to 5 groups selected from the group        consisting of (i) a halogen atom and (ii) an alkyl group which        may optionally be substituted with 1 to 3 halogen atoms (as        examples of C₆ to C₁₂ aryl or C₁ to C₁₀ heteroaryl, phenyl,        pyridyl, pyrazolyl, imidazolyl, etc. may be mentioned. As        examples of a substituent group, fluorine, chlorine, bromine,        iodine, methyl, ethyl, trifluoromethyl, etc. may be mentioned)    -   (D) C₃ to C₆ cycloalkyl which may optionally be substituted with        1 to 5 groups selected from the group consisting of (i) a        halogen atom and (ii) an alkyl group which may optionally be        substituted with 1 to 3 halogen atoms (as examples of C₃ to C₆        cycloalkyl, cyclopropyl, cyclohexyl, etc. may be mentioned. As        examples of the substituent group, fluorine, chlorine, bromine,        iodine, methyl, ethyl, trifluoromethyl, etc. may be mentioned)    -   (E) —COOR⁹ (R⁹ indicates a hydrogen atom or C₁ to C₆ alkyl) (as        specific examples, carboxyl, methoxycarbonyl, ethoxycarbonyl,        n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,        i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, etc. may        be mentioned)    -   (F) CONR¹⁰R¹¹ (where, specific examples of (a) to (d) which R¹⁰        and R¹¹ show independently are as follows)        -   (a) hydrogen atom        -   (b) C₁ to C₆ alkyl which may optionally be substituted with            1 to 3 groups selected from the group consisting of (i) a            halogen atom, (ii) C₃ to C₆ cycloalkyl, (iii) carboxyl, (iv)            C₁ to C₆ alkoxycarbonyl, (v) C₁ to C₆ alkylcarbonyl, (vi)            carbamoyl, (vii) mono-C₁ to C₆ alkylcarbamoyl, (viii) di-C₁            to C₆ alkylcarbamoyl, (ix) C₆ to C₁₂ aryl and (x) C₁ to C₁₀            heteroaryl (as specific examples of a C₁ to C₆ alkyl group,            methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,            s-butyl, t-butyl, n-pentyl, n-hexyl, etc. may be mentioned.            Here, as examples of the substituent groups (i) to (x) of a            C₁ to C₆ alkyl group,        -   (i) a halogen atom (for example, fluorine, chlorine,            bromine, iodine)        -   (ii) C₃ to C₆ cycloalkyl (for example, cyclopropyl,            cyclobutyl, cyclopentyl, cyclohexyl, etc.)        -   (iii) carboxyl        -   (iv) C₁ to C₆ alkoxycarbonyl (for example, methoxycarbonyl,            ethoxycarbonyl, etc.)        -   (v) C₁ to C₆ alkyl-carbonyl (for example, acetyl, propanoyl,            butyryl, isobutyryl, pivaroyl, etc.)        -   (vi) carbamoyl        -   (vii) mono-C₁ to C₆ alkylcarbamoyl (for example,            N-methylcarbamoyl, N-ethylcarbamoyl, etc.)        -   (viii) di-C₁ to C₆ alkylcarbamoyl (for example,            N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc.)        -   (ix) C₆ to C₁₂ aryl (for example, phenyl, tolyl, xylyl,            biphenyl, naphthyl, indenyl, etc.)        -   (x) C₁ to C₁₀ heteroaryl (for example thienyl, furyl,            pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,            thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl,            pyrazinyl, pyrimidinyl, pyridazinyl, benzothienyl,            benzofuryl, indolyl, isoindolyl, benzimidazolyl,            benzopyrazolyl, benzotriazolyl, benzothiazolyl,            benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl,            isoquinolyl, quinoxalinyl, phthalazinyl, naphthylidinyl,            purinyl, etc.) may be mentioned.)        -   (c) OR¹² (R¹² indicates a hydrogen atom or C₁ to C₆ alkyl)            (as specific examples, hydroxyl, methoxy, ethoxy, n-propoxy,            i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy,            n-pentyloxy, n-hexyloxy, etc. may be mentioned)        -   (d) (1) C₆ to C₁₄ aromatic hydrocarbon group, (2) a 5- to            8-membered aromatic heterocyclic group including 1 to 4            hetero atoms selected from a nitrogen atom, sulfur atom, and            oxygen atom, other than a carbon atom, or (3) a bicyclic or            tricyclic aromatic group formed by condensation of the above            aromatic heterocyclic group and a C₆ to C₁₄ aromatic            hydrocarbon ring (specific examples of the groups (1) to (3)            being the same as the “C₆ to C₁₄ aromatic hydrocarbon            group”, “5- to 8-membered aromatic heterocyclic group            including 1 to 4 hetero atoms selected from a nitrogen atom,            sulfur atom, and oxygen atom other than a carbon atom”, and            “bicyclic or tricyclic aromatic group formed by condensation            of the above aromatic heterocyclic group and a C₆ to C₁₄            aromatic hydrocarbon ring” in the above Ar. As preferable            examples of the groups (1) to (3) in R¹⁰ and R¹¹, phenyl,            naphthyl, pyridyl, pyrrolyl, tetrazolyl, pyrrolyl, etc. may            be mentioned)

Specific examples of the substituent groups (i) to (xxviii) which thegroups (1) to (3) may have 1 to 5 of are shown.

-   -   (i) a halogen atom (for example, fluorine, chlorine, bromine,        iodine)    -   (ii) nitro    -   (iii) cyano    -   (iv) C₁ to C₆ alkyl which may optionally be substituted with 1        to 3 halogen atoms (for example, C₁ to C₆ alkyl (for example,        methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,        t-butyl, n-pentyl, n-hexyl, etc.) which may optionally be        substituted with 1 to 3 halogen atoms selected from fluorine,        chlorine, bromine, and iodine, may be mentioned. As specific        examples, methyl, fluoromethyl, difluoromethyl, trifluoromethyl,        chloromethyl, dichloromethyl, trichloromethyl, ethyl,        2,2,2-trifluoroethyl, n-propyl, i-propyl, n-butyl, butyl,        s-butyl, t-butyl, n-pentyl, n-hexyl, etc., (preferably, methyl,        ethyl, trifluoromethyl, etc.) may be mentioned)    -   (v) C₂ to C₆ alkenyl which may optionally be substituted with 1        to 3 halogen atoms (for example, C₂ to C₆ alkenyl (for example,        vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl,        5-hexen-1-yl, etc.) which may optionally be substituted with 1        to 3 halogen atoms selected from fluorine, chlorine, bromine,        and iodine may be mentioned)    -   (vi) C₂ to C₆ alkynyl which may optionally be substituted with 1        to 3 halogen atoms (for example C₂ to C₆ alkynyl (for example,        2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.) which may        optionally be substituted with 1 to 3 halogen atoms selected        from fluorine, chlorine, bromine, and iodine may be mentioned)    -   (vii) C₃ to C₆ cycloalkyl (for example cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, etc. may be mentioned)    -   (viii) hydroxyl    -   (ix) C₁ to C₆ alkoxy which may optionally be substituted with 1        to 3 halogen atoms (for example, methoxy, ethoxy, n-propoxy,        i-propoxy, n-butoxy, i-butoxy, t-butoxy, trifluoromethyloxy,        trichloromethyloxy, etc.)    -   (x) C₁ to C₅ alkylenedioxy (for example, methylenedioxy,        ethylenedioxy, etc. may be mentioned)    -   (xi) C₁ to C₆ alkylthio which may optionally be substituted with        1 to 3 halogen atoms (for example, methylthio, ethylthio,        n-propylthio, i-propylthio, n-butylthio, i-butylthio,        s-butylthio, t-butylthio, n-pentylthio, n-hexylthio,        trifluoromethylthio, trichloromethylthio, etc. may be mentioned)    -   (xii) amino    -   (xiii) mono-C₁ to C₆ alkylamino (for example, N-methylamino,        etc. may be mentioned)    -   (xiv) di-C₁ to C₆ alkylamino (for example, N,N-dimethylamino        etc. may be mentioned)    -   (xv) 5- to 6-membered cyclic amino (for example, morpholino,        piperidino, piperazino, etc. may be mentioned)    -   (xvi) C₁ to C₆ alkylcarbonyl (for example, acetyl, propanoyl,        butyryl, isobutyryl, pivaroyl, etc. may be mentioned)    -   (xvii) carboxyl    -   (xviii) C₁ to C₆ alkoxycarbonyl (for example, methoxycarbonyl,        ethoxycarbonyl, etc. may be mentioned)    -   (xix) carbamoyl    -   (xx) thiocarbamoyl    -   (xxi) mono-C₁ to C₆ alkylcarbamoyl (for example,        N-methylcarbamoyl, N-ethylcarbamoyl, etc. may be mentioned)    -   (xxii) di-C₁ to C₆ alkylcarbamoyl (for example,        N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc. may be        mentioned)    -   (xxiii) C₆-C₁₀ arylcarbamoyl (for example, phenylcarbamoyl etc.        may be mentioned)    -   (xxiv) C₁ to C₁₀ heteroarylcarbamoyl (for example,        pyridylcarbamoyl etc. may be mentioned)    -   (xxv) sulfo    -   (xxvi) C₁ to C₆ alkylsulfonyl (for example, methanesulfonyl etc.        may be mentioned)    -   (xxvii) aminosulfonyl and    -   (xxviii) mono- or di-C₁ to C₆ alkylaminosulfonyl (for example,        N-methylaminosulfonyl etc. may be mentioned)

In the above-mentioned formula (I), as specific examples of the halogenatom expressed by R¹, R², and R³, fluorine, chlorine, bromine, andiodine may be mentioned.

In the above-mentioned formula (I), as specific examples of the C₁ to C₆alkyl group expressed by R¹, R², and R³, methyl, ethyl, n-propyl,i-propyl, n-butyl, butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc. maybe mentioned.

In the above-mentioned formula (I), as the “C₁ to C₆ alkyl group”expressed by R⁵ and R⁶, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl may be mentioned, andas the substituent group which the “C₁ to C₆ alkyl group” may have, (i)carboxyl, (ii) C₁ to C₆ alkoxy (for example, methoxy and ethoxy), (iii)C₁ to C₆ alkoxycarbonyl (for example, methoxycarbonyl andethoxycarbonyl), (iv) C₆ to C₁₂ aryloxycarbonyl (for example,phenoxycarbonyl), (v) C₁ to C₁₀ heteroaryloxycarbonyl (for example,pyridyloxycarbonyl), and (vi) amino may be mentioned. As specificexamples, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, n-pentyl, n-hexyl, methoxymethyl, ethoxymethyl, carboxymethyl,2-carboxyethyl, methoxycarbonylmethyl, 2-(methoxycarbonyl)ethyl,aminomethyl, aminoethyl, aminopropyl, etc. may be mentioned.

In the above-mentioned formula (I), as specific examples of the 3- to8-membered ring formed by R² and R³ or R⁵ and R⁶, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc. may be mentioned.

In the above-mentioned formula (I), as specific examples of the C₁ to C₆alkylcarbamoyl expressed by R⁴, N-methylaminocarbonyl,N-ethylaminocarbonyl, etc. may be mentioned.

In the above-mentioned formula (I), as specific examples of “C₁ to C₆alkyl group” expressed by R⁴, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl may bementioned, and as the 1 to 3 substituent groups which the “C₁ to C₆alkyl group” may have, (i) carbamoyl, (ii) mono- or di-C₁ to C₆alkylcarbamoyl (for example, N-methylcarbamoyl etc.), (iii) mono- ordi-C₆ to C₁₂ arylcarbamoyl, (for example, N-phenylcarbamoyl etc.), (iv)mono- or di-C₁ to C₁₀ heteroarylcarbamoyl (for example,N-pyridylcarbamoyl), (v) N—C₁ to C₆ alkyl-N—C₆ to C₁₂ arylcarbamoyl (forexample, N-methyl-N-phenylcarbamoyl), (vi) N—C₁ to C₆-alkyl-N—C₁ to C₁₀heteroarylcarbamoyl (for example, N-methyl-N-pyridylcarbamoyl), (vii)mono- or di-C₇ to C₁₆ aralkylcarbamoyl (for example, N-benzylcarbamoyl),(viii) mono- or di-C₁ to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl (forexample, N-pyridylmethylcarbamoyl etc.), (ix) carboxyl, and (x) C₁ to C₆alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, etc.) maybe mentioned. As specific examples, methyl, ethyl, n-propyl, i-propyl,carbamoylmethyl, carbamoylmethyl, N-phenylcarbamoylmethyl,N-pyridylcarbamoylmethyl, N-methyl-N-phenylcarbamoylmethyl,N-benzylcarbamoylmethyl, carbamoylethyl, N-phenylcarbamoylethyl,N-pyridylcarbamoylethyl, N-methyl-N-phenylcarbamoylethyl,N-benzylcarbamoylethyl, carboxylmethyl, carboxylethyl,methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, etc. may be mentioned.

As preferable examples of the compounds having the above-mentionedformula (I), the following may be mentioned.

1. A compound, or its salt, or a solvate thereof, where, in the formula(I), X is linear or branched C₁ to C₆ alkylene, R¹ indicates (1) ahydrogen atom, (2) halogen atom, or (3) C₁ to C₆ alkyl or R¹ forms —CH═together with X, and Y is —SO₂— or —C(═O)NH—.2. A compound, or its salt, or a solvate thereof, where, in the formula(I), Ar is a C₆ to C₁₄ aromatic hydrocarbon group.3. A compound, or its salt, or a solvate thereof, where, in the formula(I), Ar is a phenyl group, the Ar group may optionally be substitutedwith 1 to 5 groups selected from the group consisting of (i) a halogenatom, (ii) nitro, (iii) cyano, (iv) C₁ to C₆ alkyl which may optionallybe substituted with 1 to 3 halogen atoms, (v) hydroxyl, and (vi) C₁ toC₆ alkoxy which may optionally be substituted with 1 to 3 halogen atoms,and R², R³, R⁴, R⁵, and R⁶ are all hydrogen atoms.4. A compound, or its salt, or a solvate thereof, where, in the formula(I), W is a (1) C₆ to C₁₄ aromatic hydrocarbon group or (2) 5- to8-membered aromatic heterocyclic group including 1 to 4 hetero atomsselected from a nitrogen atom, sulfur atom, and oxygen atom, other thana carbon atom.5. A compound, or its salt, or a solvate thereof, where, in the formula(I), W is a (1) C₆ to C₁₄ aromatic hydrocarbon group or (2) 5- to8-membered aromatic heterocyclic group including 1 to 4 hetero atomsselected from a nitrogen atom, sulfur atom, and oxygen atom, other thana carbon atom, and Z is a (1) a bond or (2) CR⁷R⁸, where R⁷ and R⁸independently indicate,

-   -   (A) a hydrogen atom    -   (B) C₁ to C₆ alkyl which may optionally be substituted with 1 to        5 groups selected from the group consisting of (i)        carboxyl, (ii) C₁ to C₆ alkoxycarbonyl, (iii) phenyl, (iv)        hydroxyl, (v) C₁ to C₆ alkoxy, and (vi) a halogen atom.        6. A compound, or its salt, or a solvate thereof, where, in the        formula (I), W is a hydrogen atom.        7. A compound, or its salt, or a solvate thereof, where, in the        formula (I), W is a hydrogen atom, and Z is CR⁷R⁸, where R⁷ and        R⁸ independently indicate,    -   (A) a hydrogen atom    -   (B) C₁ to C₆ alkyl which may optionally be substituted with 1 to        5 groups selected from the group consisting of (i)        carboxyl, (ii) C₁ to C₆ alkoxycarbonyl, (iii) phenyl, (iv)        hydroxyl, (v) C₁ to C₆ alkoxy, and (vi) halogen atom    -   (E) —COOR⁹, where R⁹ indicates a hydrogen atom or C₁ to C₆ alkyl        or    -   (F) CONR¹⁰R¹¹, where R¹⁰ and R¹¹ independently indicate,        -   (a) a hydrogen atom        -   (b) C₁ to C₆ alkyl which may optionally be substituted with            1 to 3 groups selected from the group consisting of (i) a            halogen atom, (ii) C₃ to C₆ cycloalkyl, (iii) carboxyl, (iv)            C₁ to C₆ alkoxycarbonyl, (v) C₁ to C₆ alkyl-carbonyl, (vi)            carbamoyl, (vii) mono-C₁ to C₆ alkylcarbamoyl, (viii) di-C₁            to C₆ alkylcarbamoyl, (ix) C₆ to C₁₂ aryl, and (x) C₁ to C₁₀            heteroaryl        -   (c) OR¹², where, R¹² indicates a hydrogen atom or C₁ to C₆            alkyl or        -   (d) (1) C₆ to C₁₄ aromatic hydrocarbon group, (2) 5- to            8-membered aromatic heterocyclic group including 1 to 4            hetero atoms selected from a nitrogen atom, sulfur atom, and            oxygen atom, other than a carbon atom, or (3) a bicyclic or            tricyclic aromatic group formed by condensation of the above            aromatic heterocyclic group and a C₆ to C₁₄ aromatic            hydrocarbon ring, where the groups (1) to (3) may optionally            be substituted with 1 to 5 groups selected from the group            consisting of a (i) halogen atom, (ii) nitro, (iii)            cyano, (iv) C₁ to C₆ alkyl which may optionally be            substituted with 1 to 3 halogen atoms, (v) C₂ to C₆ alkenyl            which may optionally be substituted with 1 to 3 halogen            atoms, (vi) C₂ to C₆ alkynyl which may optionally be            substituted with 1 to 3 halogen atoms, (vii) C₃ to C₆            cycloalkyl, (viii) hydroxyl, (ix) C₁ to C₆ alkoxy which may            optionally be substituted with 1 to 3 halogen atoms, (x) C₁            to C₅ alkylenedioxy, (xi) C₁ to C₆ alkylthio which may            optionally be substituted with 1 to 3 halogen atoms, (xii)            amino, (xiii) mono-C₁ to C₆ alkylamino, (xiv) di-C₁ to C₆            alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C₁ to            C₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁ to C₆            alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi)            mono-C₁ to C₆ alkylcarbamoyl, (xxii) di-C₁ to C₆            alkylcarbamoyl, (xxiii) C₆-C₁₀ arylcarbamoyl, (xxiv) C₁ to            C₁₀ heteroarylcarbamoyl, (xxv) sulfo, (xxvi) C₁ to C₆            alkylsulfonyl, (xxvii) aminosulfonyl, and (xxviii) mono- or            di-C₁ to C₆ alkylaminosulfonyl.

As particularly preferable specific examples, the following compoundsmay be mentioned.

-   3-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic    acid, or its salt, or a solvate thereof.-   2-amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic    acid, or its salt, or a solvate thereof.-   2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic    acid, or its salt, or a solvate thereof.-   6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione,    or its salt, or a solvate thereof.-   4-[(3-amino-4-chlorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione,    or its salt, or a solvate thereof.

When the compound having formula (I) has an amine or other basic groupas a substituent group, it may also be formed a salt with an inorganicacid (for example, hydrochloric acid, hydrogen bromic acid, sulfuricacid, etc.) or a salt with an organic acid (for example, methanesulfonicacid, benzenesulfonic acid, toluenesulfonic acid, etc.) When thecompound having the formula (I) has a carboxylic acid and other acidgroup as a substituent group, it may also be formed a salt with aninorganic base (for example, sodium, potassium, calcium, magnesium, orother alkali metal or alkali earth metal etc., or ammonia etc.) or asalt with an organic base (for example, triethanolamine, 2-aminoethanol,2,2′-iminobis(ethanol), etc.).

The compound having the formula (I) or a salt thereof may also be anonsolvate or a solvate with water, methanol, ethanol, 1-propanol,2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol,3-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, formic acid,ethyl formate, acetic acid, methyl acetate, ethyl acetate, propylacetate, isobutyl acetate, acetone, methylethylketone,methylisobutylketone (preferably, water, ethanol, 1-propanol,2-propanol, 1-butanol, acetic acid, ethyl acetate, acetone, etc.) andother solvents.

[2. Method of Production of Compound Having Formula (I) or Salt orSolvate Thereof]

Below, a production method of a compound having the formula (I) or itssalt or solvate thereof will be explained. A compound having the formula(I), or its salt, or a solvate thereof may be produced by a method ofone or both of the following explained two methods of production (A) and(B).

[Method of Production (A)]

The compound having the formula (I) or a salt thereof may be produced bya cyclization reaction of a compound having the formula (II):

where Ar, W, X, Y, Z, R¹, R², R³, R⁴, R⁵, and R⁶ are the same as definedabove, Q¹ indicates a halogen atom, C₆ to C₁₀ arylsulfonyloxy groupwhich may optionally be substituted with 1 to 3 halogen atoms, or C₁ toC₄ alkylsulfonyloxy group which may optionally be substituted with 1 to3 halogen atoms.

As the group expressed by Q¹, a halogen atom (for example, chlorine,bromine, iodine, etc.), C₆ to C₁₀ arylsulfonyloxy group which mayoptionally be substituted with 1 to 3 halogen atoms (for example,benzenesulfonyloxy, p-toluene sulfonyloxy, etc.), C₁ to C₄alkylsulfonyloxy group which may optionally be substituted with 1 to 3halogen atoms (for example, methane sulfonyloxy etc.), etc. may be used.

Usually, this reaction may be carried out in the presence of a base. Asthe base, for example, sodium hydride, potassium hydride, and otheralkali metal hydrides, sodium carbonate, sodium hydrogencarbonate,potassium carbonate, potassium hydrogencarbonate, and other alkali metalcarbonates, trisodium phosphate, disodium hydrogenphosphate, sodiumdihydrogenphosphate, tripotassium phosphate, dipotassiumhydrogenphosphate, potassium dihydrogenphosphate, and other alkali metalphosphates, n-butyllithium and other organic alkali metals, lithiumdiisopropylamide and other organometallic amides, potassium t-butoxide,and other alkali metal alkoxides etc. may be used.

Further, usually, this reaction may be carried out in the presence of asolvent. As the solvent, for example, 2-propanol and other alcohols,dioxane, tetrahydrofuran, and other ethers, benzene, toluene, xylene,and other aromatic hydrocarbons, acetonitrile and other nitriles,N,N-dimethylformamide, N,N-dimethylacetoamide, N-methylpyrrolidone, andother amides, dimethylsulfoxide and other sulfoxides, etc. may be usedas single solvents or mixed solvents.

The reaction temperature of the present invention method is preferablyabout −80° C. to about 100° C., while the reaction time is preferablyabout 30 minutes to about 48 hours. Further, the reaction may be carriedout using an additive for promoting the reaction. As such an additive,for example, sodium iodide, potassium iodide, etc. may be used.

[Method of Production (B)]

Among the compounds having the formula (I) or a salt thereof, compoundswhere Y is —S(O)_(n)NH— (where n indicates an integer of 1 or 2) or—C(═O)NH— may be produced by the coupling reaction of the compound, or asalt thereof, having the formula (III):

where Ar, X, R¹, R², R³, R⁵, and R⁶ are the same as defined above, and

-   -   P indicates a protective group such as an allyl,        allyloxycarbonyl, 9-fluorenylmethylcarbonyl, linear or branched        C₁ to C₆ alkyloxycarbonyl which may optionally be substituted        with 1 to 3 halogen atoms, linear or branched C₁ to C₆        alkylcarbonyl which may optionally be substituted with 1 to 3        halogen atoms, C₇ to C₁₆ aralkyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv)        nitro, C₅ to C₁₆ arylcarbonyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv)        nitro, C₇ to C₁₆ aralkyloxycarbonyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv)        nitro, or C₅ to C₁₆ arylsulfonyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxyl, and (iv)        nitro, or R⁴, where R⁴ is as defined above,        the compound (IV), or a salt thereof, having formula (IV):

where Q² and Q³ independently indicate C₆ to C₁₀ aryloxy group which mayoptionally be substituted with 1 to 3 halogen atoms or nitro, or ahalogen atom, and Y′ indicates —S(O)_(n)— (where n indicates an integerof 1 or 2)

or C(═O),

and the compound (V), or a salt thereof, having the formula (V):

where W and Z are the same as defined as above, and the optionaldeprotection reaction of the coupling product described above.

In the production method, as the compound (V), it is possible to use acompound, or a salt thereof, having the formula (Va):

where W′ R¹⁸, and R¹⁹ are the same as defined above.

The compound (Va) may be acquired or synthesized according to the methodfor the compound (V) explained later.

As the “protective group” expressed by P, for example, allyl,allyloxycarbonyl, 9-fluorenylmethylcarbonyl, linear or branched C₁ to C₆alkyloxycarbonyl which may optionally be substituted with 1 to 3 halogenatoms (for example, t-butyloxycarbonyl etc.), linear or branched C₁ toC₆ alkylcarbonyl which may optionally be substituted with 1 to 3 halogenatoms (for example, trifluoroacetyl etc.), C₇ to C₁₆ aralkyl which mayoptionally be substituted with 1 to 3 of (i) a halogen atom, (ii) C₁ toC₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv) nitro (for example, benzyl,p-methoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, etc.), C₅to C₁₆ arylcarbonyl which may optionally be substituted with 1 to 3 of(i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv)nitro (for example, benzoyl and p-nitrobenzoyl), C₇ to C₁₆aralkyloxycarbonyl which may optionally be substituted with 1 to 3 of(i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv)nitro (for example, benzyloxycarbonyl etc.), C₅ to C₁₆ arylsulfonylwhich may optionally be substituted with 1 to 3 of (i) a halogen atom,(ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv) nitro (for example,p-toluene sulfonyl etc.) etc. may be used. When P is such a “protectivegroup”, the protective group may be removed by an ordinary method afterthe compounds (III), (IV), and (V) are reacted.

As the substituent group expressed by Q² and Q³, a C₆ to C₁₀ aryloxygroup which may optionally be substituted with 1 to 3 halogen atoms ornitro (for example, phenyloxy, p-nitrophenyloxy, p-chlorophenyloxy,2-chlorophenyloxy, etc.) or a halogen atom (for example, chlorine,bromine, iodine, etc.) etc. may be used.

The reaction used in the present invention may be a one-pot reaction ofthe compounds (III), (IV), and (V) (including the compound (Va)) in thesame system, may be a stepwise reaction, that is, a reaction of thecompound (III) and the compound (IV) followed by a reaction with thecompound (V) (including the compound (Va)), or may be a stepwisereaction, that is, a reaction of the compound (IV) and compound (V)followed by a reaction with the compound (III). When the reaction isperformed divided into two stages, it is possible to use the reactionintermediate obtained by the first stage reaction for the second stagereaction without purification, or possible to purify the reactionintermediate, then use it for the second stage reaction.

Usually, the reaction is preferably carried out in the presence of abase. When the reaction is performed divided into two stages, thereaction is preferably carried out in the presence of a base at leastone of the stages. As the base, for example sodium hydride, potassiumhydride, or other hydrated alkali metal, n-butyllithium, or otherorganic alkali metal, lithium diisopropylamide or other alkali metalamide, potassium t-butoxide or other alkali metal alkoxide,triethylamine or other alkylamine, etc. may be used.

This reaction may be carried out in inert solvent such as dioxane,tetrahydrofuran, diethylether, t-butylmethylether, or another ether,benzene, toluene, xylene, or other aromatic hydrocarbon, hexane,pentane, or other aliphatic hydrocarbon, acetonitrile or other nitrile,N,N-dimethylformamide, N,N-dimethylacetoamide, N-methylpyrrolidone, orother amide, or mixed solvents of the same.

In this reaction, the compound (IV) and compound (V) (including thecompound (Va)) preferably used in amounts of about 1 to about 5 moles,preferably about 1 to about 2 moles based upon 1 mole of the compound(III) or its salt. The reaction temperature is preferably about −100° C.to about 100° C. The reaction time is preferably about 30 minutes to 48hours.

Further, this reaction may be carried out using an additive forpromoting the reaction. As the additive, for example,4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc. may be used.

The compound (I) of the present invention or a salt thereof produced bythe method of (A) or (B) and the starting compounds (II), (III), and (V)(including compound (Va)) and synthesis intermediate for production ofthe compound (I) may be purified by known means, for example, solventextraction, pH change, solvent exchange, salting out, crystallization,recrystallization, chromatography, etc. When the compound (I) of thepresent invention, the starting compounds (II), (III), and (V)(including the compound (Va)), and the synthesis intermediate forproduction of the compound (I) (including the compound (Va)) or a saltthereof are optically active compounds and another optical isomer isincluded, a general optical resolution method may be used for separationinto the enantiomers.

It is possible, optionally, to manipulate the functional group of thecompound (I) of the present invention produced by the method of (A) or(B), to obtain a functional group converted compound (I) by 1 to 5 stepsof an ordinary reaction such as deprotection reaction when it has aprotective group, the hydrogenation reaction when X forms a double bond(—CH═) together with R¹, or other portion has a double bond, thereduction reaction when it has a nitro group, the esterificationreaction and amidation reaction when it has a carboxylic acid, thehydrolysis reaction when it has an ester group, the (i) alkylationreaction, (ii) acylation reaction, and (iii) sulfonylation reaction whenit has an amino group or hydroxyl group, the (i) alkylation reaction,(ii) acylation reaction, and (iii) sulfonylation reaction when it has aprimary or secondary amide group, and the oxidation reaction to asulfonyl group or sulfonic acid when it has an alkylthio group.

When the compound (I) of the present invention produced by the method(A) or (B) has an amine or other basic functional group as a substituentgroup, it is possible to use an ordinary method to form a salt with aninorganic acid (for example hydrochloric acid, hydrogen bromic acid,sulfuric acid, etc.) or a salt with an organic acid (for example,methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.).When the compound (I) has a carboxylic acid or other acid group as asubstituent group, it is possible to use an ordinary method to form asalt with an inorganic base (for example, sodium, potassium, calcium,magnesium, or another alkali metal, an alkali earth metal etc., ammonia,etc.) or a salt with an organic base (for example, triethanolamine,2-aminoethanol, 2,2′-imnobis(ethanol), etc.)

The compound (I) of the present invention or its salt produced by theabove method (A) or (B) may be brought into contact with, orrecrystallized from the solvent such as water, methanol, ethanol,1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol,1-pentanol, 3-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol,formic acid, ethyl formate, acetic acid, methyl acetate, ethyl acetate,propyl acetate, isobutyl acetate, acetone, methylethylketone,methylisobutylketone, or other solvent (preferably, water, ethanol,1-propanol, 2-propanol, 1-butanol, acetic acid, ethyl acetate, acetone,etc.), or other solvents, or a mixed solvent including the same so as toform its solvates.

[3. Method of Production of Starting Material for Producing the CompoundHaving Formula (I) or a Salt or Solvate Thereof]

A production method of the starting material compounds (II), (III), and(V) (including the compound (Va)) used for the production of thecompound (I), or its salt, or a solvate thereof, and the productionmethod of the starting compound (VI) (including the compound (VIa)) forthe production of the compounds (II), (III) will be explained.

The starting compound (II) may, for example, be obtained by the methodof the scheme:

where Ar, W, X, Y, Z, P, Q¹, R¹, R², R³, R⁴, R⁵, and R⁶ are the same asdefined above,

-   -   Y″ indicates an isocyanate group (—NCO), halocarbonyl group (for        example, chlorocarbonyl, bromocarbonyl, etc.), halosulfonyl        group (for example, chlorosulfonyl, bromosulfonyl, etc.), or a        C₆ to C₁₀, aryloxycarbonyl group which may optionally be        substituted with 1 to 3 halogen atoms or nitro (for example,        4-nitrophenylcarbonyl, 2-chlorophenylcarbonyl,        2,4-dichlorophenylcarbonyl, etc.),    -   P′ indicates a protective group such as an allyl,        allyloxycarbonyl, 9-fluorenylmethylcarbonyl, a linear or        branched C₁ to C₆ alkyloxycarbonyl which may optionally be        substituted with 1 to 3 halogen atoms, linear or branched C₁ to        C₆ alkylcarbonyl which may optionally be substituted with 1 to 3        halogen atoms, C₇ to C₁₆ aralkyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv)        nitro, C₅ to C₁₆ arylcarbonyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv)        nitro, C₇ to C₁₆ aralkyloxycarbonyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv)        nitro, or C₅ to C₁₆ arylsulfonyl which may optionally be        substituted with 1 to 3 groups selected from (i) a halogen        atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv)        nitro, or a hydrogen atom, and    -   Q⁵ indicates a halogen atom or OH.

First, from the compound (VI), for example a condensation reaction usinga general condensing agent (for example, DCC, 1,1′-carbonyl diimidazole,etc.), the Yamaguchi method, or other known method may be used forcondensation with the compound (VIII) to obtain the compound (X).Alternatively, from the compound (VI), for example, a condensationreaction with ammonia using a general condensing agent (for example,DCC, 1,1′-carbonyl diimidazole, etc.) or other known method to obtainthe compound (VII), and subsequent reaction of obtained compound (VII)with the compound (IX) in the presence of sodium hydride, potassiumt-butoxide, or other bases may also be used to obtain the compound (X).

Next, from the obtained compound (X), if necessary, the ordinarily-useddeprotection reaction for removing the P′ group, and then, when Q⁵ incompound (XI) is a halogen atom, for example a reaction with thecompound (XI) in the presence of triethylamine, sodium hydroxide, orother base or, when Q⁵ in compound (XI) is an OH group, for example, acondensation reaction with the compound (XI) using a general condensingagent (for example DCC etc.) may be used to obtain the compound (II). Atthis time, when P is not R⁴ but a protective group, before or after thereaction of the above-mentioned compound (X) and compound (XI), it ispossible to remove the P group by an ordinary method for conversion to acompound where R⁴ is a hydrogen atom.

In the above method of production, as the compound (VI), it is possibleto use a compound of the formula (VIa):

{where R¹, R², R³, P, P′, X′, R²⁰, R²¹, R²², R²³, and R²⁴ are the sameas defined above.

However, the following compounds are excluded:

(1) Compounds wherein R²⁰ and R²⁴ are chlorine atoms and R²¹, R²², andR²³ are hydrogen atoms,(2) Compounds wherein R²⁰, R²², and R²⁴ are methyl and R²¹ and R²³ arehydrogen atoms, and(3) Compounds wherein R²⁰ is a chlorine atom or bromine atom and R²¹,R²², R²³, and R²⁴ are hydrogen atoms}.

The compound (VIa) may be acquired or synthesized according to themethod for the compound (VI) explained later.

The compound (IX) used in above-mentioned reaction may be a commerciallyavailable product or known compound. The compound (IX) used inabove-mentioned reaction, for example, may be one synthesized by a knownchlorosulfonylation reaction etc. described in J. Am. Chem. Soc., 1940,62, 511 or Chem. Ber., 1957, 90, 841, etc. The compound (IX) may also beone synthesized from a known carboxylic acid compound by, for example,the known acid chloride synthesis method. Further, the compound (IX) mayalso be synthesized from the compound (V) (including the compound (Va))by for example the known isocyanate synthesis method using diphosgene,triphosgene, etc.

The compound (VIII) used in above-mentioned reaction may be acommercially available product or known compound. Further, the compound(VIII) may be obtained by the compound (IX) by, for example, acondensation reaction with ammonia or other known method. The compound(VIII) can be obtained by, for example, the known aminosulfonylationreaction described in Bioorg. Med. Chem. Lett., 2003, 13 (5), 837 etc.

The starting compound (III) may, for example, be synthesized by themethod of the scheme:

where Ar, X, P, P′, R¹, R², R³, R⁵, R⁴, and R⁶ are the same as definedabove, and R¹⁶ indicates a C₁ to C₆ alkyl group or C₇ to C₁₆ aralkylgroup.

First, it is possible to use a condensation reaction, for example, thereaction using a generally used condensing agent (for example, DCC etc.)or other known reaction, for condensation of the compound (VI) andcompound (XII) or its salt to obtain the compound (XIII). The compound(XII) used in this reaction may be a commercially available product orknown amino acid derivative.

Next, from the obtained compound (XIII), for example, a hydrolysisreaction using sodium hydroxide etc. or other known method may be usedfor hydrolysis to obtain the compound (XIV). If necessary at this time,before and/or after the hydrolysis reaction, for example, a known methodusing an acid, base, etc. may be used to remove the P′, but this is notabsolutely necessary when P′ is a hydrogen atom.

Next, from the obtained compound (XIV), for example, a condensingreaction using a general condensing agent (for example, DCC etc.) orother known method may be used for cyclization reaction to obtain thecompound (III).

In the above production method, as the compound (VI), theabove-mentioned compound (VIa) may also be used.

Among the starting compounds (III), a compound where X is an oxygenatom, NR¹³, or —S(O)_(m)— (where m indicates an integer of 0 to 2) maybe synthesized by the method shown in, for example, the scheme:

where Ar, P, P′, R¹, R², R³, R⁵, R⁴, R⁶, and R¹⁶ are thesame as defined above, Q⁶ together with the adjoining oxygen atomindicates C₆ to C₁₀ arylsulfonyloxy which may optionally be substitutedwith 1 to 3 halogen atoms or C₁ to C₄ alkylsulfonyloxy which mayoptionally be substituted with 1 to 3 halogen atoms. Here, X indicatesan oxygen atom, NR¹³, or —S(O)m-, where m indicates an integer of 0 to2.

That is, from a commercially available or known β-alanine derivative(XV), for example, a reaction for introducing the protective group,reductive alkylation reaction or other known method which is used ingeneral for amino groups may be used to introduce a P group (protectivegroup or R⁴ group) or optionally a P′ group (protective group orhydrogen atom) to obtain the compound (XVI). Next, for example, acondensation reaction using a general condensing agent (for example, DCCetc.) or other known method may be used to condense the compound (XVI)and the compound (XII) or its salt to obtain the compound (XVII), thenthe hydroxyl group of obtained compound (XVII) converted to a leavinggroup, that is, a OQ⁶ group, to obtain the compound (XVIII). Further, itis possible to perform a nuclear substitution reaction using thecompound (XIX) on the obtained compound (XVIII) to obtain the compound(XIII). From the obtained compound (XIII), it is possible to use themethods described above to obtain the compound (III).

The starting compound (III) may be synthesized by the method shown in,for example, the scheme:

where Ar, X, R¹, R², R³, R⁴, R⁵, R⁶, P, and P′ have the same meaning asabove. R¹⁵ indicates a C₁ to C₆ alkyl group or C₇ to C₁₆ aralkyl group,and P″ indicates a protective group, the same or different, such asallyl, allyloxycarbonyl, 9-fluorenylmethylcarbonyl, linear or branchedC₁ to C₆ alkyloxycarbonyl which may optionally be substituted with 1 to3 halogen atoms, linear or branched C₁ to C₆ alkylcarbonyl which mayoptionally be substituted with 1 to 3 halogen atoms, C₇ to C₁₆ aralkylwhich may optionally be substituted with 1 to 3 of (i) a halogen atom,(ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv) nitro, C₅ to C₁₆arylcarbonyl which may optionally be substituted with 1 to 3 of (i) ahalogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv) nitro,C₇ to C₁₆ aralkyloxycarbonyl which may optionally be substituted with 1to 3 of (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy,or (iv) nitro, C₅ to C₁₆ arylsulfonyl which may optionally besubstituted with 1 to 3 of (i) a halogen atom, (ii) C₁ to C₆ alkyl,(iii) C₁ to C₆ alkoxy, or (iv) nitro.

First, from the compound (VI), for example, an esterification reactionusing a general condensing agent (for example, DCC etc.), and subsequentdeprotection of the P′ group, or other known method may be used toobtain the compound (XX).

Next, from the compound (XX), for example, a condensation reaction usinga general condensing agent (for example, DCC etc.) and other knownmethod may be used to condense the compound (XXI) to obtain the compound(XXII). The starting compound (XXI) used in this reaction may be acommercially available product or known amino acid derivative.

Next, from the compound (XXII), for example a deprotection reactionusing an acid, base, etc. or other known method may be used to removethe P″ group and R¹⁵ group simultaneously or in stages so as to obtainthe compound (XXIII).

Next, from the compound (XXIII), for example, condensation reactionusing a general condensing agent (for example, DCC etc.) or other knownmethod may be used for cyclization reaction to obtain the compound(III).

In the above production method, as the compound (VI), theabove-mentioned compound (VIa) may be used.

The starting compound (V) used in above-mentioned reactions may be acommercially available product or known compound. Further, among thestarting compounds (V), a compound where W is not a hydrogen atom and Zis CR⁷R⁸, where R⁸ is a hydrogen atom, may also be synthesized by themethod of the scheme:

where W has the same definition as the above-mentioned W (but W is not ahydrogen atom), Z is CR⁷R⁸, R⁸ is a hydrogen atom, R⁷ is the same asdefined above, Q⁷ indicates a halogen atom, and Q⁸ indicates a halogenatom, a C₆ to C₁₀ arylsulfonyloxy group which may optionally besubstituted with 1 to 3 halogen atoms, or a C₁ to C₄ alkylsulfonyloxygroup which may be substituted with 1 to 3 halogen atoms.

First, from the starting compound (XXIV), for example, a couplingreaction with nitroalkane using a palladium catalyst (for example,palladium acetate, tris(dibenzylideneacetone)dipalladium) or anothertransition metal catalyst, or other known method may be used to obtainthe compound (XXV).

Next, from the compound (XXV), for example, an Nef reaction or otherknown method may be used to obtain the compound (XXVI). The compound(XXVI) can be obtained by an alkylation reaction, using organometallicreagent etc., of an acid chloride, Weinreb amide, or other reactivecompound, which can be obtained from the compound (XXIX) by using aknown method. Above-mentioned starting material compounds (XXIV) and(XXIX) used can be commercially available products or known compounds.

Next, from the compound (XXVI), for example a reduction reaction usingsodium boron hydride or other generally used reducing agent may be usedto obtain the compound (XXVII). At this time, for example, theasymmetric reduction reaction described in Angew. Chem. Int. Ed., 1998,37, 1986, J. Org. Chem., 1985, 50, 5446, etc. may be used to obtain anoptically active compound (XXVII). The compound (XXVII) can also beobtained from the compound (XXX) by, for example, an alkylation reactionusing a Grignard reagent or other organometallic reagent. At this time,for example the asymmetric alkylation reaction described in Chem. Rev.,2001, 101, 757 etc. may be used to obtain the optically active compound(XXVII). Above-mentioned starting material compounds (XXVI) and (XXX)used may be commercially available products or known compounds.

Next, from the compound (XXVII), for example, an alkylsulfonylationreaction, arylsulfonylation reaction, halogenation reaction, or otherknown method may be used for conversion of hydroxyl group of compound(XXVII) to a generally used leaving group to obtain the compound(XXVIII).

Next, from the compound (XXVIII), for example, a substitution reactionusing sodium azide, potassium phthalimide, or other suitable nitrogennucleophilic agent to obtain an amine precursor, and subsequent reactionfor obtained amine precursor such as a reduction, hydrolysis etc. may beused to obtain the compound (V). The above-mentioned amine precursor maybe directly obtained by, for example, Mitsunobu reaction or other methodfrom the compound (XXVII). The compound (V) may also be obtained by, forexample, hydrogenation etc. of oxime which can be obtained from thecompound (XXVI) by a known method. Further, from the compound (XXVI),for example, an asymmetric amination reaction described in Angew. Chem.Int. Ed., 2003, 42 (44), 5472 etc. may be used to obtain an opticallyactive compound (V).

It is possible, optionally, to manipulate the functional group of thecompound (V) to obtain a functional group converted compound (V) by 1 to5 steps of an ordinary reaction such as deprotection reaction when ithas a protective group, a hydrogenation reaction when it has an alkenylgroup or alkynyl group, a reduction when it has a nitro group, anesterification reaction and amidation reaction when it has a carboxylicacid, a hydrolysis when it has an ester group, (i) alkylation reaction,(ii) acylation reaction, and (iii) sulfonylation reaction when it has anamino group or hydroxyl group, (i) alkylation reaction, (ii) acylationreaction, and (iii) sulfonylation reaction when it has a primary orsecondary amide group, and an oxidation reaction to a sulfonyl group orsulfonic acid when it has an alkylthio group, etc.

Among the starting material compounds (V), a compound expressed by theformula (Va):

where W′, R¹⁸ and R¹⁹ are the same as defined above may also besynthesized according to the production method of the compound (V) usingthe corresponding starting compound.

When the compounds (V) and (Va) obtained by the above methods haveasymmetric centers, it is possible to use an ordinary method for opticalresolution to obtain an enantiomer of one of the compounds (V) and (Va).

Next, the synthesis method of the compound (VI) as the common startingmaterial for producing the compounds (II) and (III) will be explained.

Among the compounds (VI), a compound where R¹ forms —CH═ together withX, or a compound where R¹ is a hydrogen atom and X is an alkylene may besynthesized by the method of scheme:

where Ar, P, P′, R², and R³ are the same as defined above,

-   -   R¹⁷ indicates C₁ to C₆ alkyl or C₇ to C₁₆ aralkyl, X″ indicates        a bond or C₁ to C_(s) alkylene,    -   Q⁴ together with the adjoining oxygen atom indicates C₆ to C₁₀        arylsulfonyloxy which may optionally be substituted with 1 to 3        halogen atoms, C₁ to C₄ alkylsulfonyloxy which may optionally be        substituted with 1 to 3 halogen atoms, C₁ to C₆        alkylcarbonyloxy, or C₇ to C₁₆ aralkylcarbonyloxy. Here, R¹        forms —CH═, together with X, or R¹ is a hydrogen atom and X is        alkylene.

That is, a coupling reaction of the compound (XXXI) and compound(XXXII), for example, the Baylis-Hillman reaction and other knownmethod, and if necessary, subsequent conversion of a free hydroxyl groupetc. of coupling product to a leaving group, that is, OQ⁴ group may beused for a reaction to obtain the compound (XXXIII). The startingcompound (XXXI) or (XXXII) used in this reaction may be a commerciallyavailable product or known compound. Among the compounds (XXXII), acompound where X″ is a bond may be obtained by formylation reaction, forexample, a Vilsmeier reaction or other known method, of a commerciallyavailable or known aromatic compound. Next, from the obtained compound(XXXIII), for example, an azidation reaction using sodium azide etc. orother known method may be used for conversion to the compound (XXXIV),then for example a Staudinger reaction, hydrogenation, or other knownmethod may be used for reduction of an azide group of compound (XXXIV),and optionally a double bond, to obtain the compound (XXXV). Further,from the obtained compound (XXXV), for example, a reaction forintroduction of a protective group, reductive alkylation reaction, orother known method used in general for an amino group may be used tointroduce a P group (protective group or R⁴ group), and optionally a P′group (protective group or hydrogen atom), and further, for example, ahydrolysis reaction using sodium hydroxide etc. or another known methodmay be used for hydrolysis to obtain the compound (VI). Further, fromthe compound (XXXV), it is also possible to first perform a hydrolysisreaction, then perform a reaction to introduce a P group (optionally, aP′ group) so as to obtain the compound (VI).

Among the compounds (VI), a compound where R² and R³ both indicatehydrogen atoms can also be synthesized by the method of the scheme:

where, Ar, X, P, P′, R¹, and R¹⁷ have the same meaning as above. Q⁹ isC₆ to C₁₀ arylsulfonyloxy which may optionally be substituted with 1 to3 halogen atoms, C₁ to C₄ alkylsulfonyloxy which may optionally besubstituted with 1 to 3 halogen atoms, or a halogen atom. R² and R³ bothindicate a hydrogen atom here. For example, it is possible to use thecompound (XXXVI) as a starting material to obtain a compound (XXXVII)having the leaving group Q⁹ by using a series of known method, which is,for example, selective hydrolysis of one ester moiety of compound(XXXVI), conversion of the resulting carboxylic acid to acid chloride,selective reduction of the acid chloride to alcohol, and a sulfonylationreaction or halogenation reaction. Next, from the obtained compound(XXXVII), for example an azidation reaction using sodium azide or otherknown method may be used to obtain the compound (XXIV). From theobtained compound (XXXIV), the above-mentioned method may be used toobtain the compound (VI). The starting compound (XXXVI) may be easilyobtained by a substitution reaction of the ArX group on a commerciallyavailable or known halomalonic acid ester, a Knoevenagel reaction from acommercially available or known malonic acid ester, an alkylationreaction of a malonic acid ester, or other generally used known reactionor, if necessary, subsequent hydrogenation reaction for above obtainedcompound using a transition metal catalyst or other known method.

Among the compounds (VI), a compound where R² and R³ both indicatehydrogen atoms can also be synthesized by the method of the scheme:

where, Ar, X, P, P′, R¹, and R¹⁷ are the same as defined above, and R²and R³ both indicate a hydrogen atom. That is, for example, by using acompound (XXXVIII) as a starting material, which is easily obtained by asubstitution reaction of an ArX group on a commercially available orknown halocyanoacetic acid ester, a Knoevenagel reaction of acommercially available or known cyanoacetic acid ester, an alkylationreaction of a cyanoacetic acid ester, or other generally used knownreaction or, if necessary, subsequent hydrogenation reaction using atransition metal catalyst or other known method, it is possible toselectively reduce the nitrile groups by, for example, the methoddescribed in J. Am. Chem. Soc., 1982, 104, 6801, to obtain the compound(XXXV) or its salt. From the obtained compound (XXXV), theabove-mentioned methods may be used to obtain the compound (VI).

Among the compounds (VI), a compound where R¹ forms —CH═ together withX, or R¹ is a hydrogen atom and X indicates alkylene can also besynthesized by the scheme:

where R²⁵ indicates halogenated alkyl, for example, a halogenated methylgroup, and Ar, P, P′, R², R³, R¹⁷, and X″ are the same as defined above.Here, R¹ forms —CH═ together with X, or R¹ is hydrogen and X is analkylene. That is, it is also possible to synthesize the compound (VI)by an alkylation reaction of the compound (XXXIX) using the compound(XL) and the succeeding hydrolysis reaction. Further, an aldol reactionof the compound (XXXIX) and compound (XXXII) may be used for conversionto the compound (XLI), then a dehydration, deoxygenation, or other knownreaction, and the following hydrolysis reaction may be used forsynthesis of the compound (VI). The starting materials used in thisreaction, that is, the compounds (XXXIX), (XL), and (XXXII), can becommercially available products or known compounds. The compound (XXXIX)may be used one synthesized by using a reaction for introduction of aprotective group, reductive alkylation reaction, or other known reactionused in general for an amino group, to introduce a P group (protectivegroup or R⁴ group) and, optionally, a P′ group (protective group orhydrogen atom) to a commercially available or known n-amino acid ester.

Among the compounds (XXXII), a compound where X″ is a bond may besynthesized by formylation reaction, for example a Vilsmeier reaction orother known method, of a commercially available or known aromaticcompound.

Among the compounds (VI), a compound where R¹ forms —CH═ together withX, or R¹ is a hydrogen atom and X is alkylene can also be synthesized bythe scheme:

where, Ar, R², R³, R¹⁷, P, P′, Q⁴, and X″ are the same as defined above.Here, R¹ forms —CH═ together with X, or R¹ is a hydrogen atom and X isalkylene. That is, from the above-mentioned compound (XXXIII), it ispossible to synthesize the compound (VI) where R¹ forms —CH═, togetherwith X by the reaction with PP′—NH₂, and subsequent hydrolysis usingsodium hydroxide etc. or other known method. Further, before or afterhydrolysis in this reaction, it is possible to perform a hydrogenationreaction using for example a transition metal catalyst, or other knownmethod to synthesize a compound (VI) where R¹ is a hydrogen atom and Xis an alkylene.

Among the compounds (VI), a compound having the formula (VIa):

where R¹, R², R³, P, P′, X, R²⁰, R²¹, R²², R²³, and R²⁴ are the same asdefined above, and except for the following compounds:(1) Compounds where R²⁰ and R²⁴ are chlorine atoms and R²¹, R²², and R²³are hydrogen atoms,(2) Compounds where R²⁰, R²², and R²⁴ are methyl and R²¹ and R²³ arehydrogen atoms, and(3) Compounds where R²⁰ is a chlorine atom or bromine atom and R²¹, R²²,R²³, and R²⁴ are hydrogen atoms can also be synthesized using thecorresponding starting compounds according to the production method ofthe compound (VI).

Among the compounds (VI), a compound, where X is an oxygen atom, NR¹³,or —S(O)m- can be synthesized by the method described in, for example,J. Org. Chem., 1994, 59, 3123, Tetrahedron, 1987, 43 (17), 3881, Chem.Lett., 1997, 4, 375 or Tetrahedron Lett., 1991, 32 (27), 3151.

It is possible, optionally, to manipulate the functional group of thecompound (VI) or compound (VIa) obtained by the above methods to producea functional group converted compound (VI) or compound (VIa) by 1 to 5steps of an ordinary reaction such as a deprotection reaction when ithas a protective group, a hydrogenation reaction when it has an alkenylgroup or alkynyl group, a reduction reaction when it has a nitro group,an esterification reaction and amidation reaction when it has ancarboxylic acid, a hydrolysis reaction when it has an ester group, an(i) alkylation reaction, (ii) acylation reaction, and (iii)sulfonylation reaction when it has an amino group or hydroxyl group, an(i) alkylation reaction, (ii) acylation reaction, and (iii)sulfonylation reaction when it has a primary or secondary amide group,and an oxidation reaction to a sulfonyl group, sulfonic acid, etc. whenit has an alkylthio group.

When the compounds (VI) and (VIa) obtained by the above-mentionedmethods include asymmetric centers, it is also possible use an ordinarymethod for optical resolution to obtain an enantiomer of one of thecompounds (VI) and (VIa).

The compound (I), or its salt or a solvate thereof of the presentinvention, have superior chymase inhibitory activity and have lowtoxicity (LD₅₀>1 g/kg), so can be safely used for mammals (for example,humans, rat, mice, dogs, cattle, etc.) for the prevention and/ortreatment of bronchial asthma, urticaria, atopic dermatitis, allergicconjunctivitis, rhinitis, rheumatoid arthritis, mastocytosis,scleroderma, heart failure, cardiac hypertrophy, congestive heartfailure, hypertension, atherosclerosis, myocardial ischemia, myocardialinfarction, restenosis after PTCA, restenosis after bypass graftsurgery, ischemic peripheral circulatory disorders, hyperaldosteronism,diabetic retinopathy, diabetic nephropathy, nephritis,glomerulosclerosis, renal insufficiency, psoriasis, solid tumor,postoperative adhesion, glaucoma, and ocular hypertension, and otherdiseases.

The administration route of the pharmaceutical for prevention ortreatment of above-mentioned diseases may be oral or parenteral.

The preparation used in the present invention may also contain, asactive ingredients, other pharmaceutical ingredients in addition to thecompound (I) or its pharmaceutically acceptable salt or solvate thereof.

As such a pharmaceutical active ingredient, for example, steroids (forexample, betamethasone etc.), immunosuppressants (for example,tacrolimus, pimecrolimus etc.), antiallergic agent (clemastine fumarate,d-chlorpheniramine maleate, cyproheptadine hydrochloride, promethazinehydrochloride, homochlorcyclizine hydrochloride, mequitazine,diphenhydramine hydrochloride, ebastine, cetirizine hydrochloride,olopatadine hydrochloride, fexofenadine hydrochloride, sodiumcromoglicate, emedastine difumarate, suplatast tosilate, epinastinehydrochloride, etc.) etc. may be mentioned. These ingredients are notparticularly limited so long as the object of the present invention isachieved, and may be used in approximate ratios. As specific examples ofthe dosage forms, for example, tablets (including sugar-coated tabletsand film-coated tablets), pills, capsules (including microcapsules),granules, fine subtilaes, powders, syrups, emulsions, suspensions,injections, inhalants, ointments, eye drops, etc. may be used. Thesedrug products may be prepared according to ordinary methods (forexample, methods described in the Japan Pharmacopeia etc.)

In the preparations of the present invention, the content of thecompound according to the present invention differs according to thetype of the preparation, but usually is about 0.01 to about 100% byweight, based upon the total weight of the preparation, preferably about0.1 to about 50% by weight, more preferably about 0.5 to about 20% byweight or so.

Specifically, tablets can be produced by granulating a homogenousmixture of pharmaceutical as it is or with an excipient, binder,disintegrating agent, or other suitable additives by a suitable method,then adding a lubricant agent, and subjecting the mixture to compressiveshaping; directly subjecting a homogenous mixture of pharmaceutical asit is or with an excipient, binder, disintegrating agent, or othersuitable additives by a suitable method, to compressive shaping; ordirectly subjecting a homogenous mixture of granules of pharmaceuticalas it is prepared in advance or with suitable additives, to compressiveshaping. Further, these tablets may, if necessary, be given a coloringagent, flavoring agent, and may be coated with a suitable coating agent.

As the production method of an injections, it is possible to dissolve,suspend, or emulsify a certain amount of the pharmaceutical in injectionwater, physiological saline, Ringer's solution, etc. in the case of awater-based solvent, or in an ordinary vegetable oil etc. in the case ofa non-water-based solvent, to obtain a certain volume, or to take acertain amount of the pharmaceutical and seal it in an injection usecontainer.

As the carriers for oral preparations, for example starch, mannitol,crystalline cellulose, sodium carboxylmethylcellulose, and othersubstances commonly used in the field of preparations may be used. Asthe carriers for injections, for example, distilled water, physiologicalsaline, glucose solution, transfusions, etc. may be used. In addition,it is possible to suitably add additives generally used in preparations.

The dosage of these preparations differs according to age, body weight,symptoms, route of administration, number of dosages, etc., but forexample for an adult patient, daily dose of these preparation is usuallyabout 0.1 to about 100 mg/kg, preferably about 1 to 50 mg/kg, morepreferably about 1 to about 10 mg/kg, based on daily dose of activeingredient (the compound of the present invention), administered orallyonce or in three portions daily.

EXAMPLES

Reference Examples, Examples, and Test Examples will now be used toexplain the present invention in more detail, but the present inventionis not limited thereto. The fractions including the desired substancesin the Examples and Reference Examples were detected by TLC (thin-layerchromatography). In TLC observation, As a TLC plate, a Merch 60F₂₅₄ wasused, while as the detection method, a UV detector was used. For the MS,the ESI method (i.e., electron spray ionization method) was used todetect the positive ions.

Reference Example 1 5-chloro-2-anisaldehyde (compound S1)

To 5-chloro-2-salicylaldehyde (10 g) in an N,N-dimethylformamide (70 ml)solution, methyl iodide (8 ml) and potassium carbonate (9 g) were addedand the mixture was stirred at room temperature for 3 hours. Distilledwater was added to the reaction solution and the mixture was extractedwith diethylether. The organic layer was successively washed withsaturated sodium thiosulfate aqueous solution, distilled water, andsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was dried in vacuo to obtain the titlecompound (9.1 g).

NMR (CDCl₃): δ10.4 (1H, s), 7.78 (1H, d, J=2.7 Hz), 7.48 (1H, dd, J=8.9,2.7 Hz), 6.94 (1H, d, J=8.9 Hz), 3.93 (3H, s)

Reference Example 2 methyl2-[(5-chloro-2-methoxyphenyl)(hydroxy)methyl]propenoate (compound S2)

A reaction mixture of the compound S1 (7 g), methyl acrylate (6 ml),1,4-diazabicyclo[2.2.2]octane (4.6 g), lanthanumtrifluoromethanesulfonate (1.2 g), and diethanol amine (2.7 ml) wasstirred at room temperature for 60 hours. Distilled water and saturatedpotassium hydrogensulfate aqueous solution were added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was successively washed with distilled water and saturated saline,dried over with anhydrous sodium sulfate, then concentrated. The residuewas dried in vacuo to obtain the title compound (11.1 g).

NMR (CDCl₃): δ7.37 (1H, d, J=2.9 Hz), 7.22 (1H, dd, J=8.7, 2.9 Hz), 6.8(1H, d, J=8.7 Hz), 6.31 (1H, m), 5.83 (1H, d, J=5.8 Hz), 5.69 (1H, m),3.81 (3H, s), 3.77 (3H, s)

Reference Example 3 methyl2-[(5-chloro-2-methoxyphenyl)(acetoxy)methyl]propenoate (compound S3)

To the compound S2 (11 g) in methylene chloride (100 ml) solution,pyridine (3.5 ml) and acetylchloride (3.1 ml) were added under icecooling and the mixture was stirred at that temperature for 1 hour.Distilled water was added to the reaction solution, methylene chloridewas distilled off in vacuo, and the remaining aqueous layer wasextracted with ethyl acetate. The organic layer was successively washedwith saturated potassium hydrogensulfate aqueous solution, distilledwater, saturated sodium hydrogencarbonate aqueous solution, andsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was dried in vacuo to obtain the titlecompound (11.8 g).

Reference Example 4 methyl(2E)-2-(azidemethyl)-3-(5-chloro-2-methoxyphenyl)-2-propenoate (compound S4)

To the compound S3 (11.8 g) in dimethylsulfoxide (70 ml) solution,sodium azide (3.9 g) was added and the mixture was stirred at roomtemperature for 30 minutes. Distilled water was added to the reactionsolution, and the mixture was extracted with diethylether. The organiclayer was successively washed with distilled water and saturated saline,dried over with anhydrous sodium sulfate, and concentrated. The residuewas dried in vacuo to obtain the title compound (10.1 g).

Reference Example 5(2E)-2-(aminoethyl)-3-(5-chloro-2-methoxyphenyl)-2-propenoic acid(compound S5)

To the compound S4 (10 g) in tetrahydrofuran (70 ml) solution,triphenylphosphine (9.4 g) and distilled water (1 ml) were added and themixture was stirred at room temperature for 15 hours. Next,tetrahydrofuran was distilled off in vacuo, methanol (70 ml) and 2Nsodium hydroxide aqueous solution (35 ml) were added to the remainingmixture, and the mixture was stirred at room temperature for 2 hours.Next, the methanol was distilled off in vacuo and the remaining aqueouslayer was washed with ethyl acetate. Further, the aqueous layer wasneutralized by hydrochloric acid, then precipitate was collected byfiltration, was washed with diethylether, and was dried in vacuo toobtain the title compound (6.3 g).

Reference Example 6(2E)-3-(5-chloro-2-methoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S6)

To the compound S5 (3 g) in tetrahydrofuran (15 ml) suspension,anhydrous trifluoroacetic acid (2.3 ml) was added under ice cooling andthe mixture was stirred at room temperature for 2 hours. The reactionsolution was concentrated, ethyl acetate was added to the residue, andthe obtained solution was successively washed with saturated potassiumhydrogensulfate aqueous solution and saturated saline and dried overwith anhydrous sodium sulfate and concentrated. The residue wasrecrystallized from ethyl acetate/hexane to obtain the title compound(3.07 g).

NMR (CDCl₃): δ8.01 (1H, s), 7.39 (1H, d, J=2.4 Hz), 7.35 (1H, dd, J=8.8,2.4 Hz), 7.01 (1H, br), 6.88 (1H, d, J=8.8 Hz), 4.33 (2H, d, J=6 Hz),3.84 (3H, s)

MS: 360 (M+Na)⁺

Reference Example 7(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-phenyl-2-propenoic acid(compound S7)

Instead of the starting material in Reference Example 2, that is, thecompound S1, benzaldehyde was used for the similar procedure as inReference Example 2 to Reference Example 4. To the obtainedmethyl(2E)-2-(azide methyl)-3-phenyl-2-propenoate (1.62 g) intetrahydrofuran (20 ml) solution, triphenylphosphine (1.96 g) anddistilled water (0.2 ml) were added and the mixture was stirred at roomtemperature for 6 hours. Next, di-tert-butyldicarbonate (1.72 g) wasadded to the reaction solution, the mixture was stirred at roomtemperature for 15 minutes, then the reaction solution was concentrated.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=4/1). To 1 g of the obtainedmethyl(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-phenyl-2-propenoate(1.68 g), ethanol (8 ml) and 2M sodium hydroxide aqueous solution (2 ml)were added and the mixture was stirred at room temperature for 2 hours.The reaction solution was diluted with distilled water, and the ethanolwas distilled off in vacuo. The obtained aqueous solution was madeacidic by a 10% potassium hydrogensulfate aqueous solution and themixture was extracted with diethylether. The organic layer wassuccessively washed with distilled water and saturated saline, driedover with anhydrous sodium sulfate, and concentrated to obtain the titlecompound (818 mg).

NMR (CDCl₃): δ7.98-7.73 (1H, br), 7.60-7.30 (5H, br), 6.75 (0.5H, brs),5.14 (0.5H, brs), 4.25 (2H, d, J=5.9 Hz), 1.60-1.15 (9H, br)

MS: 278 (M+H)⁺

Reference Example 8(2E)-3-phenyl-2-{[(trifluoroacetyl)amino]methyl}-2-propenoic acid(compound S8)

Instead of the starting material in Reference Example 2, that is, thecompound S1, benzaldehyde was used for successively the similarprocedures as in Reference Example 2 to Reference Example 6 to obtainthe title compound.

NMR (DMSO-d₆): δ12.79 (1H, brs), 9.64 (1H, br), 7.81 (1H, s), 7.53-7.35(5H, m), 4.18 (2H, d, J=4.2 Hz)

Reference Example 9(2E)-3-(5-chloro-2-nitrophenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S9)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 5-chloro-2-nitrobenzaldehyde was used for successively thesimilar procedures as in Reference Example 2 to Reference Example 6 toobtain the title compound.

NMR (CDCl₃): δ8.24 (1H, d, J=8.8 Hz), 8.19 (1H, s), 7.58 (1H, dd, J=8.8,2.2 Hz), 7.51 (1H, d, J=2.2 Hz), 7.05 (1H, br), 4.16 (2H, d, J=6.3 Hz)

MS: 375 (M+Na)⁺

Reference Example 10(2E)-3-(5-fluoro-2-methoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S10)

Instead of the starting material compound in Reference Example 1, thatis, the 5-chloro-2-salicylaldehyde, 5-fluoro-2-hydroxybenzaldehyde wasused for successively the similar procedures as in Reference Example 1to Reference Example 6 to obtain the title compound.

NMR (CDCl₃): δ8.05 (1H, s), 7.21 (1H, dd, J=8.6, 3 Hz), 7.14-6.96 (2H,m), 6.88 (1H, dd, J=9.1, 4.3 Hz), 4.35 (2H, d, J=5.9 Hz), 3.84 (3H, s)

MS: 344 (M+Na)⁺

Reference Example 11(2E)-3-(2-methoxymethoxy-5-methylphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S11)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 2-methoxymethoxy-5-methylbenzaldehyde was used forsuccessively the similar procedures as in Reference Example 2 toReference Example 6 to obtain the title compound.

NMR (DMSO-d₆): δ12.72 (1H, brs), 9.60 (1H, br), 7.87 (1H, s), 7.17 (1H,d, J=8.3 Hz), 7.09 (1H, s), 7.06 (1H, d, J=8.3 Hz), 5.20 (2H, s), 4.12(2H, d, J=4.4 Hz), 3.36 (3H, s), 2.22 (3H, s)

MS: 370 (M+Na)⁺

Reference Example 12(2E)-3-(3-chloro-5-fluoro-2-methoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S12)

Instead of the starting material compound in Reference Example 1, thatis, the 5-chloro-2-salicylaldehyde,3-chloro-5-fluoro-2-hydroxybenzaldehyde was used for successively thesimilar procedures as in Reference Example 1 to Reference Example 6 toobtain the title compound.

NMR (CDCl₃): δ8.00 (1H, s), 7.22 (1H, dd, J=7.6, 2.7 Hz), 7.15 (1H, dd,J=8.6, 2.7 Hz), 7.10 (1H, br), 4.34 (2H, d, J=6.1 Hz), 3.78 (3H, s)

MS: 378 (M+Na)⁺

Reference Example 13(2E)-3-(5-chloro-2-ethoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S13)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 5-chloro-2-ethoxybenzaldehyde was used for successively thesimilar procedures as in Reference Example 2 to Reference Example 6 toobtain the title compound.

NMR (CDCl₃): δ8.04 (1H, s), 7.40 (1H, d, J=2.5 Hz), 7.32 (1H, dd, J=8.9,2.5 Hz), 7.02 (1H, br), 6.86 (1H, d, J=8.9 Hz), 4.36 (2H, d, J=6 Hz),4.07 (2H, q, J=6.9 Hz), 1.41 (3H, t, J=6.9 Hz)

MS: 374 (M+Na)⁺

Reference Example 14(2E)-3-(2-methoxy-5-trifluoromethylphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S14)

Instead of the starting material compound in Reference Example 2, thatis, the compound S2,2-methoxy-5-trifluoromethylbenzaldehyde was used forsuccessively the similar procedures as in Reference Example 2 toReference Example 6 to obtain the title compound.

NMR (DMSO-d₆): δ12.90 (1H, brs), 9.67 (1H, t, J=4.4 Hz), 7.82 (1H, s),7.77 (1H, dd, J=8.7, 2.1 Hz), 7.62 (1H, d, J=2.1 Hz), 7.28 (1H, d, J=8.7Hz), 4.04 (2H, d, J=4.4 Hz), 3.90 (3H, s)

MS: 394 (M+Na)⁺

Reference Example 15(2E)-3-(4-chloro-5-fluoro-2-methoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S15)

To 2-chloro-1-fluoro-4-methoxybenzene (5 g) in methylene chloride (30ml) solution, titanium tetrachloride (5.8 ml) andα,α-dichloromethylmethylether (2.8 ml) were added under ice cooling, themixture was stirred at 2° C. for 11.5 hours, then the reaction solutionwas poured into ice. Next, the methylene chloride layer was separated,washed with saturated saline, dried over with anhydrous sodium sulfate,and concentrated. The obtained residue was recrystallized fromethylether. The thus obtained 4-chloro-5-fluoro-2-methoxybenzaldehyde(3.41 g) was used instead of the starting material in Reference Example2, that is, the compound S1, for successively the similar procedure asin Reference Example 2 to Reference Example 6 to obtain the titlecompound.

NMR (CDCl₃): δ7.96 (1H, s), 7.37 (1H, d, J=9.0 Hz), 7.06 (1H, br), 6.96(1H, d, J=5.9 Hz), 4.33 (2H, d, J=6.1 Hz), 3.84 (3H, s)

MS: 378 (M+Na)⁺

Reference Example 16(2E)-3-(2,5-dimethoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S16)

Instead of the starting material compound of Reference Example 1, thatis, the 5-chloro-2-salicylaldehyde, 2,5-dihydroxybenzaldehyde was usedfor successively the similar procedure as in Reference Example 1 toReference Example 6 to obtain the title compound.

NMR (CDCl₃): δ8.11 (1H, s), 7.11 (1H, br), 7.03 (1H, d, J=2.9 Hz), 6.95(1H, dd, J=9.0, 2.9 Hz), 6.88 (1H, d, J=9.0 Hz), 4.39 (2H, d, J=5.9 Hz),3.82 (6H, s)

MS: 356 (M+Na)⁺

Reference Example 17(2E)-3-benzo[1,3]-dioxol-5-yl-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S17)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 3,4-methylenedioxybenzaldehyde was used for successivelythe similar procedure as in Reference Example 2 to Reference Example 6to obtain the title compound.

NMR (CDCl₃): δ7.89 (1H, s), 7.12-7.03 (1H, m), 7.10 (1H, d, J=1.6 Hz),7.04 (1H, dd, J=8.1, 1.6 Hz), 6.89 (1H, d, J=8.1 Hz), 6.04 (2H, s), 4.49(2H, d, J=5.9 Hz)

MS: 340 (M+Na)⁺

Reference Example 18(2E)-3-(2-fluoro-5-methoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S18)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 2-fluoro-5-methoxybenzaldehyde was used for successivelythe similar procedure as in Reference Example 2 to Reference Example 6to obtain the title compound.

NMR (CDCl₃): δ8.00 (1H, s), 7.12 (1H, dd, J=5.8, 3.1 Hz), 7.11-7.02 (1H,m), 7.06 (1H, t, J=9.1 Hz), 6.98-6.91 (1H, m), 4.41 (2H, d, J=6 Hz),3.85 (3H, s)

MS: 344 (M+Na)⁺

Reference Example 19(2E)-3-(2-chlorophenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S19)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 2-chlorobenzaldehyde was used for successively the similarprocedure as in Reference Example 2 to Reference Example 6 to obtain thetitle compound.

NMR (DMSO-d₆): δ12.98 (1H, brs), 9.59 (1H, br), 7.79 (1H, s), 7.59-7.53(1H, m), 7.52-7.48 (1H, m), 7.47-7.38 (2H, m), 4.08 (2H, d, J=4.7 Hz)

Reference Example 20(2E)-3-(3,5-dichlorophenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S20)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 3,5-dichlorobenzaldehyde was used for successively thesimilar procedure as in Reference Example 2 to Reference Example 6 toobtain the title compound.

NMR (DMSO-d₆): δ12.98 (1H, brs), 9.64 (1H, t, J=4.7 Hz), 7.72 (1H, s),7.65 (1H, t, J=1.9 Hz), 7.525 (1H, d, J=1.9 Hz), 7.523 (1H, d, J=1.9Hz), 4.13 (2H, d, J=4.7 Hz)

Reference Example 21(2E)-3-(5-chloro-2-ethoxymethoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S21)

To 5-chloro-2-salicylaldehyde (25 g) in methylene chloride (250 ml)solution, ethoxymethylchloride (15 ml) and N,N-diisopropylethylamine (33ml) were added under ice cooling and the mixture was stirred at roomtemperature for 4 hours. The reaction solution was concentrated, thenthe residue was diluted with diethylether and the insoluble compound wasfiltered out. The filtrate was successively washed with distilled water,1N sodium hydroxide aqueous solution, and saturated saline, dried overwith anhydrous sodium sulfate, then concentrated. The thus obtained5-chloro-2-ethoxymethoxybenzaldehyde as a crude product (32.4 g) wasused for the similar procedure as in Reference Example 2 to ReferenceExample 6 to obtain the title compound.

NMR (CDCl₃): δ8.02 (1H, s), 7.40 (1H, d, J=2.4 Hz), 7.33 (1H, dd, J=8.9,2.4 Hz), 7.16 (1H, d, J=8.9 Hz), 7.05 (1H, br), 5.23 (2H, s), 4.36 (2H,d, J=6 Hz), 3.71 (2H, q, J=7.0 Hz), 1.22 (3H, t, J=7.0 Hz)

MS: 404 (M+Na)⁺

Reference Example 22(2E)-3-(2-methoxy-5-methoxymethoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S22)

To 2,5-dihydroxybenzaldehyde (15 g) in acetone (105 ml) solution,methoxymethyl chloride (8.25 ml) in ethyl acetate (16.5 ml) solution andpotassium carbonate (15 g) were added under ice cooling and the mixturewas stirred at room temperature for 17 hours. Saturated ammoniumchloride aqueous solution was added to the reaction solution, then themixture was extracted with ethyl acetate. The organic layer was washedwith saturated saline, then was extracted with 1N sodium hydroxideaqueous solution. The aqueous layer was neutralized by 1N hydrochloricacid, then the mixture was extracted with ethyl acetate. The organiclayer was dried over with anhydrous sodium sulfate, then concentrated.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=4/1). The thus obtained2-hydroxy-5-methoxymethoxybenzaldehyde (1.75 g) was used for the similarprocedure as in Reference Example 1 to Reference Example 6 to obtain thetitle compound.

NMR (CDCl₃): δ8.09 (1H, s), 7.14-7.00 (3H, m), 6.87 (1H, d, J=8.8 Hz),5.16 (2H, s), 4.36 (2H, d, J=5.7 Hz), 3.82 (3H, s), 3.48 (3H, s)

MS: 386 (M+Na)⁺

Reference Example 23(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(5-chloro-2-methoxyphenyl)-2-propenoicacid (compound S23)

To the compound S5 (15 g) in tetrahydrofuran (300 ml) suspension, 2Nsodium hydroxide aqueous solution (70 ml) and di-tert-butyldicarbonate(15 g) were added and the mixture was stirred at room temperature for 1hour. Next, tetrahydrofuran was distilled off in vacuo, the obtainedaqueous mixture was acidified by adding saturated potassiumhydrogensulfate aqueous solution, then the mixture was extracted withethyl acetate. The organic layer was washed with saturated saline anddried over with anhydrous sodium sulfate and concentrated. The residuewas recrystallized from ethyl acetate/hexane to obtain the titlecompound (19.8 g).

NMR (CDCl₃): δ7.93 (0.5H, br), 7.78 (0.5H, br), 7.42 (0.5H, br), 7.30(1H, dd, J=8.8, 2.4 Hz), 7.19 (0.5H, br), 6.84 (1H, d, J=8.8 Hz), 6.76(0.5H, br), 5.12 (0.5H, br), 4.14 (2H, br), 3.84 (3H, s), 1.55-1.15 (9H,m)

MS: 364 (M+Na)⁺

Reference Example 24(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(4-cyanophenyl)-2-propenoicacid (compound S24)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 4-cyanobenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

NMR (DMSO-d₆): δ12.77 (1H, brs), 7.89 (2H, d, J=8.4 Hz), 7.70-7.62 (3H,m), 6.94 (1H, br), 3.90 (2H, d, J=4.6 Hz), 1.36 (9H, s)

MS: 303 (M+H)⁺

Reference Example 25(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(naphthyl-2-yl)-2-propenoicacid (compound S25)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 2-naphthylaldehyde was used for the similar procedure as inReference Example 2 to Reference Example 5 and Reference Example 23 toobtain the title compound.

NMR (CDCl₃): δ8.12-7.94 (2H, m), 7.92-7.80 (3H, m), 7.68-7.58 (1H, m),7.58-7.50 (2H, m), 5.20 (1H, brs), 4.35 (2H, d, J=6 Hz), 1.48 (9H, br)

MS: 350 (M+Na)⁺

Reference Example 26(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(4-fluorophenyl)-2-propenoicacid (compound S26)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 4-fluorobenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

NMR (CDCl₃): δ7.85-7.31 (2H, m), 7.12 (2H, t, J=8.2 Hz), 6.72 (1H, br),5.16 (1H, br), 4.22 (2H, d, J=6.1 Hz), 1.28 (9H, br)

MS: 318 (M+Na)⁺

Reference Example 27(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(4-chlorophenyl)-2-propenoicacid (compound S27)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 4-chlorobenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

NMR (CDCl₃): δ7.82-7.70 (1H, m), 7.48-7.22 (3H, m), 6.77 (1H, br), 5.14(1H, br), 4.21 (2H, d, J=6.3 Hz), 1.28 (9H, br)

MS: 334 (M+Na)⁺

Reference Example 28(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(3-chlorophenyl)-2-propenoicacid (compound S28)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 3-chlorobenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

NMR (CDCl₃): δ7.85-7.65 (2H, m), 7.51-7.35 (2H, m), 6.80 (1H, br), 5.10(1H, br), 4.21 (2H, d, J=3.5 Hz), 1.258 (9H, br)

MS: 334 (M+Na)⁺

Reference Example 29(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(3-methylphenyl)-2-propenoicacid (compound S29)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 3-methylbenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

NMR (DMSO-d₆): δ12.56 (1H, brs), 7.62 (1H, s), 7.35-7.25 (3H, m), 7.20(1H, d, J=7.1 Hz), 6.87 (1H, br), 3.93 (2H, d, J=4.7 Hz), 2.32 (3H, s),1.39 (9H, s)

MS: 314 (M+Na)⁺

Reference Example 30(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(3-trifluoromethylphenyl)-2-propenoicacid (compound S30)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 3-trifluoromethylbenzaldehyde was used for the similarprocedure as in Reference Example 2 to Reference Example 5 and ReferenceExample 23 to obtain the title compound.

NMR (DMSO-d₆): δ12.75 (1H, brs), 7.87 (1H, s), 7.81-7.71 (3H, m), 7.66(1H, t, J=7.7 Hz), 6.98 (1H, br), 3.89 (2H, d, J=4.3 Hz), 1.37 (9H, s)

MS: 368 (M+Na)⁺

Reference Example 31(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(3-cyanophenyl)-2-propenoicacid (compound S31)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 3-cyanobenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

NMR (DMSO-d₆): δ12.78 (1H, brs), 7.94 (1H, s), 7.84 (1H, d, 7.6 Hz),7.80 (1H, d, 7.8 Hz), 7.66-7.60 (2H, m), 6.97 (1H, br), 3.90 (2H, d, 4.2Hz), 1.37 (9H, s)

MS: 325 (M+Na)⁺

Reference Example 32(2E)-2-{[(allyloxycarbonyl)amino]methyl}-3-(4-methoxymethoxyphenyl)-2-propenoicacid (compound S32)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 4-methoxymethoxybenzaldehyde was used for the similarprocedure as in Reference Example 2 to Reference Example 4. To theobtained compound (6.1 g) in tetrahydrofuran (70 ml) solution,triphenylphosphine (5.8 g) and distilled water (0.6 ml) were added andthe mixture was stirred at room temperature for 13 hours. 2Nhydrochloric acid (10 ml) was added to the reaction solution, thentetrahydrofuran was distilled off in vacuo. The obtained aqueoussolution was washed with ethyl acetate, then a 4N sodium hydroxideaqueous solution (20 ml) was added. Tetrahydrofuran (50 ml) was added tothis, allyl chlorocarbonate (2.8 ml) was added under ice cooling, andthe mixture was stirred at room temperature for 3 hours. Thetetrahydrofuran was distilled off in vacuo, then ethanol (50 ml) and a4N sodium hydroxide aqueous solution (10 ml) were added to the obtainedaqueous mixture and the mixture was stirred at room temperature for 18hours. The ethanol was distilled off in vacuo, then the obtained aqueousmixture was washed with diethylether-hexane (3:1), was acidified byadding a potassium hydrogensulfate aqueous solution, and was extractedwith diethylether. The organic layer was successively washed with waterand saturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was recrystallized from diethylether/hexane toobtain the title compound (3.8 g).

NMR (CDCl₃): δ7.86 (1H, s), 7.56 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1Hz), 6.00-5.88 (1H, m), 5.39 (1H, br), 5.36-5.15 (4H, m), 4.58 (2H, d,J=5 Hz), 4.32 (2H, d, J=5.9 Hz), 3.48 (3H, s)

MS: 344 (M+Na)⁺

Reference Example 33N-(tert-butoxycarbonyl)-2-(3-chlorobenzyl)-β-alanine (compound S33)

To a suspension of the compound S28 (500 mg) and platinum oxide (50 mg)in methanol (25 ml) was stirred under hydrogen atmosphere at roomtemperature for 45 minutes. The insoluble compound was filtered out,then the filtrate was concentrated to obtain the title compound as acrude product (440 mg).

NMR (CDCl₃): δ7.30-7.00 (4H, m), 4.94 (1H, br), 3.43-3.20 (2H, m),3.10-2.60 (3H, m), 1.45 (9H, s)

MS: 336 (M+Na)⁺

Reference Example 34 methyl3-(benzoylamino)-2-[(5-chloro-2-methoxyphenyl)(hydroxy)methyl]butanoate(compound S34)

To methyl 3-(benzoylamino)butanoate (1.65 g) in tetrahydrofuran (30 ml)solution, lithium diisopropylamide (2Mheptane/tetrahydrofuran/ethylbenzene solution) (8.2 ml) was added at−78° C. and the mixture was stirred at −45° C. for 30 minutes. Thereaction solution was again cooled to −78° C., then the compound ofReference Example 1 (1.5 g) in tetrahydrofuran (3 ml) solution was addedand, while gradually raising the temperature to room temperature, themixture was stirred for 16 hours. Saturated ammonium chloride solutionwas added to the reaction solution, then tetrahydrofuran was distilledoff in vacuo. The remaining solution was extracted with ethyl acetate.The organic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) toobtain the title compound (2.27 g).

Reference Example 35 methyl6-(5-chloro-2-methoxyphenyl)-4-methyl-2-phenyl-5,6-dihydro-4H-1,3-oxazine-5-carboxylate(compound S35)

To the compound S34 (3.07 g) in trifluoroacetic acid (7 ml) solution,concentrated sulfuric acid (0.4 ml) was added and the mixture wasstirred at room temperature for 1 hour. 2N sodium hydroxide aqueoussolution was added to the reaction solution and the mixture concentratedin vacuo. The residue was diluted with ethyl acetate, then the obtainedsolution was successively washed with distilled water, saturated sodiumhydrogencarbonate aqueous solution, and saturated saline, dried overwith anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=2/1)to obtain the title compound (2.17 g) as a mixture of two types ofdiastereomers (A and B).

(Diastereomer A)

NMR (CDCl₃): δ7.95-7.90 (2H, m), 7.47-7.31 (4H, m), 7.28 (1H, dd, J=8.8,2.6 Hz), 6.84 (1H, d, J=8.8 Hz), 5.64 (1H, d, J=10.5 Hz), 4.02 (1H, dd,J=10.5, 6.7 Hz), 3.79 (3H, s), 3.55 (3H, s), 2.64 (1H, t, J=10.5 Hz),1.34 (3H, d, J=6.7 Hz)

(Diastereomer B)

NMR (CDCl₃): δ7.93 (2H, d, J=7.2 Hz), 7.47-7.31 (3H, m), 7.29-7.24 (1H,m), 7.2 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.7 Hz), 5.83 (1H, d, J=6.9Hz), 3.92 (1H, dd, J=6.7, 5.5 Hz), 3.83 (3H, s), 3.66 (3H, s), 3.24 (1H,dd, J=6.9, 5.5 Hz), 1.32 (3H, d, J=6.7 Hz)

Reference Example 36methyl(2E)-2-[1-(benzoylamino)ethyl]-3-(5-chloro-2-methoxyphenyl)-2-propenoate(compound S36)

To the compound S35 (2.17 g) in tetrahydrofuran (20 ml) solution,potassium tert-butoxide (0.69 g) was added and the mixture was stirredat room temperature for 2 hours. Saturated potassium hydrogensulfateaqueous solution was added to the reaction solution, then the mixturewas extracted with ethyl acetate. The organic layer was successivelywashed with saturated saline, dried over with anhydrous sodium sulfate,then concentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1 to 1/1) to obtain the titlecompound (0.44 g).

NMR (CDCl₃): δ7.80-7.75 (2H, m), 7.71 (1H, s), 7.58-7.38 (5H, m), 7.3(1H, dd, J=8.8, 1.4 Hz), 6.84 (1H, d, J=8.8 Hz), 5.56-5.45 (1H, m), 3.86(3H), 3.81 (3H), 1.47 (3H, d, J=7 Hz)

Reference Example 37methyl(2E)-2-{1-[benzoyl(tert-butoxycarbonyl)amino]ethyl}-3-(5-chloro-2-methoxyphenyl)-2-propenoate(compound S37)

To the compound S36 (400 mg) in tetrahydrofuran (3 ml) solution,4-dimethylaminopyridine (88 mg) and di-tert-butyl-dicarbonate (1.5 g)were added in three additions during stirring at room temperature over28 hours, then the reaction solution was diluted with ethyl acetate, waswashed with saturated potassium hydrogensulfate aqueous solution, driedover with anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=5/1)to obtain the title compound (413 mg).

Reference Example 38methyl(2E)-2-{1-[(tert-butoxycarbonyl)amino]ethyl}-3-(5-chloro-2-methoxyphenyl)-2-propenoate(compound S38)

To the compound S37 (400 mg) in tetrahydrofuran (2 ml) solution, 2Nlithium hydroxide aqueous solution (2 ml) and methanol (4 ml) were addedand the mixture was stirred at room temperature for 8 hours. Themethanol and tetrahydrofuran were distilled off in vacuo. The reactionsolution was diluted with ethyl acetate, then the mixture was washedwith saturated potassium hydrogensulfate aqueous solution, dried overwith anhydrous sodium sulfate, then concentrated. The residue wasrecrystallized from hexane/ethyl acetate to obtain the title compound(211 mg).

NMR (CDCl₃): δ7.76 (1H, br), 7.29 (1H, dd, J=8.9, 2.4 Hz), 7.29-7.22(2H, m), 6.84 (1H, d, J=8.9 Hz), 4.92 (1H, br), 3.83 (3H, s), 1.60-1.15(3H, m)

Reference Example 39ethyl(2E)-3-(5-chloro-2-methoxyphenyl)-2-cyano-2-propenoate (compoundS39)

To the compound S1 (500 mg) and methyl cyanoacetate (497 mg) in ethanol(10 ml) solution, sodium ethoxide (300 mg) was added under ice coolingand the mixture was stirred at room temperature for 2 hours. Saturatedammonium chloride aqueous solution was added to the reaction solution,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was diluted with hexane/diethylether, then theprecipitated solid was collected by filtration to obtain the titlecompound (730 mg).

Reference Example 40 ethyl3-(5-chloro-2-methoxyphenyl)-2-cyanopropanoate (compound S40)

To the compound S39 (591 mg) in ethanol (18 ml) solution, 5% platinumcarbon (sulfided catalyst) (118 mg) was added and the mixture wasstirred under hydrogen atmosphere at room temperature for 4 hours. Theinsoluble compound was filtered out, then the filtrate was concentrated.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=3/1) to obtain the title compound (313 mg).

Reference Example 41 methyl3-(5-chloro-2-methoxyphenyl)-2-cyano-2-methylpropanoate (compound S41)

To the compound S40 (301 mg) in methanol (6 ml) solution, sodiummethoxide (0.54 mg) and methyl iodide (0.14 ml) were added and themixture was stirred at room temperature for 3 hours. The reactionsolution was concentrated, then chloroform and saturated ammoniumchloride aqueous solution were added to the residue. The organic layerwas separated, then washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1) to obtainthe title compound (147 mg).

NMR (CDCl₃): δ7.23 (1H, dd, J=8.8, 2.6 Hz), 7.14 (1H, d, J=2.6 Hz), 6.81(1H, d, J=8.8 Hz), 3.8 (3H, s), 3.79 (3H, s), 3.21 (1H, d, J=13.5 Hz),3.15 (1H, d, J=13.5 Hz), 1.6 (3H, s)

Reference Example 42 methyl3-amino-2-(5-chloro-2-methoxybenzyl)-2-methylpropanoate (compound S42)

To the compound S41 (147 mg) and cobalt (II) chloride 6 hydrate (261 mg)in methanol (7.4 ml) solution, sodium boron hydride (208 mg) was addedin several additions batches and the mixture was stirred at roomtemperature for 30 minutes. 2N hydrochloric acid was added to thereaction solution, methanol was distilled off in vacuo, and theremaining solution was washed with ethyl acetate. A 1N sodium hydroxideaqueous solution was added to the aqueous layer, and the mixture wasextracted with ethyl acetate. The organic layer was successively washedwith saturated saline, dried over with anhydrous sodium sulfate, andconcentrated to obtain the title compound (71 mg).

NMR (CDCl₃): δ7.2 (1H, dd, J=8.8, 2.5 Hz), 7.03 (1H, d, J=2.5 Hz), 6.92(1H, d, J=8.8 Hz), 3.79 (3H, s), 3.68 (3H, s), 3.34-3.29 (2H, m), 2.91(2H, br), 1.18 (3H, s)

Reference Example 43 2-(5-chloro-2-methoxybenzyl)-2-methyl-β-alanine(compound S43)

To the compound S42 (60 mg) in methanol (0.6 ml) solution, 1N sodiumhydroxide aqueous solution (0.3 ml) was added and the mixture wasstirred at 60° C. for 1.5 hours. The methanol was distilled off invacuo, 1N hydrochloric acid was added to the remaining solution toacidify (pH was 4), and the mixture was washed with ethyl acetate. Theaqueous layer was stirred for a while, and the precipitated solid wascollected by filtration to obtain the title compound (32.4 mg).

Reference Example 442-(5-chloro-2-methoxybenzyl)-2-methyl-N-(trifluoroacetyl)-β-alanine(compound S44)

To the compound S43 (32 mg) in tetrahydrofuran (0.32 ml) solution,anhydrous trifluoroacetic acid (26 μl) was added and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated, then the residue was diluted with ethyl acetate and washedwith saturated saline. The organic layer was concentrated, the residuewas diluted with hexane/ethyl acetate, and the precipitated solid wascollected by filtration to obtain the title compound (33.8 mg).

NMR (CDCl₃): δ7.29 (1H, br), 7.21 (1H, dd, J=8.8, 2.7 Hz), 7.12 (1H, d,J=2.7 Hz), 6.82 (1H, d, J=8.8 Hz), 3.83 (3H, s), 3.44 (1H, dd, J=14.0,6.9 Hz), 3.38 (1H, dd, J=14.0, 6.2 Hz), 3.03 (1H, d, J=13.9 Hz), 2.92(1H, d, J=13.9 Hz), 1.29 (3H, s)

Reference Example 45 diethyl 2-(5-chloro-2-methoxybenzyl)malonate(compound S45)

To the compound S1 (23 g) in toluene (230 ml) solution, diethyl malonate(20 ml) and piperadine acetate (3.9 g) were added. The mixture wasstirred at reflux for 4 hours with Dean-Stark apparatus for removingwater. The reaction solution was successively washed with distilledwater and saturated saline, dried over with anhydrous sodium sulfate,then concentrated. The residue was dissolved in ethanol (450 ml),platinum oxide (2 g) was added to the solution, then the mixture wasstirred at room temperature under hydrogen atmosphere at 5 atm for 14hours. The insoluble compound was filtered out, then the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1) to obtain the title compound(39 g).

Reference Example 46 diethyl2-(5-chloro-2-methoxybenzyl)-2-fluoromalonate (compound S46)

To the compound S45 (39 g) in tetrahydrofuran (400 ml) solution, sodiumhydride (60% mineral oil dispersion) (5 g) was added under ice coolingand the mixture was stirred at that temperature for 1 hour. Next,N-fluoro-2,4,6-trimethylpiperidium trifurate (36 g) was added to thereaction solution and the mixture was stirred at room temperature for 4hours. Saturated potassium hydrogensulfate aqueous solution was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) toobtain the title compound (43 g).

NMR (CDCl₃): δ7.20-7.14 (2H, m), 6.75 (1H, d, J=7.0 Hz), 4.32-4.19 (4H,m), 3.76 (3H, s), 3.5 (2H, d, J=23.4 Hz), 1.31-1.22 (6H, m)

Reference Example 47 monoethyl2-(5-chloro-2-methoxybenzyl)-2-fluoromalonate (compound S47)

To the compound S46 (41 g) in tetrahydrofuran (200 ml)/ethanol (200 ml)solution, 1N sodium hydroxide aqueous solution (125 ml) was added andthe mixture was stirred at room temperature for 24 hours. The reactionsolution was concentrated, diethylether was added to the residue, andthe mixture was extracted with distilled water. The aqueous layer wasneutralized by 1N hydrochloric acid, and the mixture was extracted withdiethylether. The organic layer was washed with saturated saline, driedover with anhydrous sodium sulfate, and concentrated to obtain the titlecompound (27 g).

Reference Example 48 ethyl2-(5-chloro-2-methoxybenzyl)-2-fluoro-3-hydroxypropanoate (compound S48)

To the compound S47 (14 g) in methylene chloride (420 ml) solution,N,N-dimethylformamide (1 drop) and oxalyl chloride (25 ml) were added,the mixture was stirred under heating and reflux for 2 hours, then thereaction solution was concentrated. To the residue in tetrahydrofuran(420 ml) solution, lithium tri-tert-butoxy aluminum hydride (15.5 g) wasadded at −78° C. and the mixture was stirred at that temperature for 1.5hours. To the reaction solution, a Rochelle salt aqueous solution wasadded, then the mixture was stirred for 30 minutes and was extractedwith ethyl acetate. The organic layer was washed with saturated saline,dried over with anhydrous sodium sulfate, then concentrated. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=2/1 to 1/1) to obtain the title compound (5 g).

Reference Example 49 ethyl3-azide-2-(5-chloro-2-methoxybenzyl)-2-fluoropropanoate (compound S49)

To the compound S48 (2.43 g) in methylene chloride (48 ml) solution,2,6-di-tert-butyl-4-methylpyridine (2.57 g) and trifluoromethanesulfonic acid anhydride (2.1 ml) were added under ice cooling and themixture was stirred at that temperature for 30 minutes. Distilled waterwas added to the reaction solution and the mixture was extracted withchloroform. The organic layer was washed with saturated saline, driedover with anhydrous sodium sulfate, then concentrated. The residue wasdiluted with chloroform, the insoluble compound was filtered out, andthe filtrate was concentrated. To the residue in N,N-dimethylformamide(48 ml) solution, sodium azide (1.09 g) was added and the mixture wasstirred at 60° C. for 1 hour. Distilled water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=3/1) to obtain the titlecompound (1.64 g).

NMR (CDCl₃): δ7.21 (1H, dd, J=8.8, 2.3 Hz), 7.16 (1H, d, J=2.3 Hz), 6.78(1H, d, J=8.8 Hz), 4.32-4.19 (2H, m), 3.79 (3H, s), 3.67 (1H, dd,J=28.2, 13.4 Hz), 3.5 (1H, dd, J=14.7, 13.4 Hz), 3.29 (1H, dd, J=21.0,14.3 Hz), 3.12 (1H, dd, J=21.1, 14.3 Hz), 1.27 (3H, t, J=7.2 Hz)

Reference Example 503-azide-2-(5-chloro-2-methoxybenzyl)-2-fluoropropanoic acid (compoundS50)

To the compound S49 (1.64 g) in tetrahydrofuran (16 ml)/methanol (16 ml)solution, 2N sodium hydroxide aqueous solution (8 ml) was added and themixture was stirred at room temperature for 1 hour. Saturated potassiumhydrogensulfate aqueous solution was added the reaction solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated saline, dried over with anhydrous sodium sulfate,then concentrated. The residue was diluted with hexane/ethyl acetate,then the precipitate was collected by filtration to obtain the titlecompound (1.36 g).

Reference Example 51N-(tert-butoxycarbonyl)-2-(5-chloro-2-methoxybenzyl)-2-fluoro-β-alanine(compound S51)

To the compound S50 (1.36 g) in tetrahydrofuran (14 ml) solution,distilled water (0.14 ml) and triphenylphosphine (1.24 g) were addedunder ice cooling and the mixture was stirred at room temperature for 5hours. The reaction solution was concentrated, ethyl acetate was addedto the residue, and the precipitate was collected by filtration. To thefiltrate in tetrahydrofuran (15 ml) solution, 2N sodium hydroxideaqueous solution (6.5 ml) and di-tert-butyl-dicarbonate (1.5 g) wereadded and the mixture was stirred at room temperature for 4 hours.Saturated potassium hydrogensulfate aqueous solution was added to thereaction solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (ethyl acetate tochloroform/methanol=3/1) to obtain the title compound (1.43 g).

NMR (CDCl₃): δ7.22-7.15 (2H, m), 6.78 (1H, d, J=9.1 Hz), 3.78 (3H, s),3.57-3.01 (5H, m), 1.42 (9H, s)

Reference Example 52 tert-butyl(6-chloro-2-oxo-2H-chromen-3-yl)methylcarbamate (compound S52)

To the compound S5 (5.0 g) in acetic acid (90 ml) solution, 30% hydrogenbromide/acetic acid solution (10 ml) was added and the mixture wasstirred at 100° C. for 63 hours. The precipitated solid was collected byfiltration, 1,4-dioxane (27 ml), a 4M sodium hydroxide aqueous solution(5.4 ml), and di-tert-butyl-dicarbonate (2.2 g) were added, and themixture was stirred at room temperature for 2 hours. The 1,4-dioxane wasdistilled off in vacuo, distilled water (30 ml) was added, and 1Nhydrochloric acid was added to adjust the pH to 5. The precipitatedsolid was collected by filtration to obtain the title compound (2.82 g).

NMR (CDCl₃): δ7.63 (1H, s), 7.48-7.42 (2H, m), 7.30-7.24 (1H, m), 5.24(1H, br), 4.19 (2H, d, J=6.5 Hz), 1.44 (9H, s)

Reference Example 53(2Z)-2-{[(tert-butoxycarbonyl)amino]ethyl}-3-(2-butoxy-5-chlorophenyl)-2-propenoicacid (compound S53)

To the compound S52 (2.0 g), methanol (40 ml), tetrahydrofuran (40 ml),and 4M sodium hydroxide (3.9 ml) were added and the mixture was stirredfor 2 hours. 4M sodium hydroxide (1 ml) was additionally added and themixture was stirred for 15 minutes, then the reaction solution wasconcentrated. To 700 mg of the obtained residue, N,N-dimethylformamide(7 ml) and n-butyl iodide (0.55 ml) were added and the mixture wasstirred at room temperature for 16 hours. The reaction solution wasconcentrated, distilled water was added, and the mixture was extractedwith ethyl acetate. The organic layer was successively washed withsaturated sodium hydrogencarbonate aqueous solution and saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated.Methanol (6.5 ml), tetrahydrofuran (6.5 ml), and 1M sodium hydroxide(6.5 ml) were added to the residue, and the mixture was stirred at roomtemperature for 21 hours. Methanol and tetrahydrofuran were distilledoff in vacuo, distilled water was added, then 1N hydrochloric acid wasadded to the obtained aqueous solution to adjust the pH to 4 and themixture was extracted with chloroform. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, andconcentrated to obtain the title compound (560.9 mg).

Reference Example 54 Methyl 5-(aminosulfonyl)-2-chlorobenzoate (compoundS54)

To methyl 5-amino-2-chlorobenzoate (16.2 g) in concentrated hydrochloricacid (40 ml)/acetic acid (120 ml) suspension, a sodium nitrite (7.6 g)aqueous solution (20 ml) was added under ice cooling and the mixture wasstirred at that temperature for 45 minutes. Next, the inside temperatureof the reaction vessel was cooled to −5° C., copper (II) chloride2-hydrate (3.7 g) and a 21% sulfur dioxide in acetic acid solution (60ml) were added, and the mixture was raised to room temperature andstirred at 12 hours. Under ice cooling, distilled water was added to thereaction solution, the mixture was stirred at that temperature for 30minutes, and the precipitate was collected by filtration. The filtratewas dissolved in tetrahydrofuran (50 ml), 28% ammonia water (10 ml) wasadded under ice cooling, and the mixture was stirred at that temperaturefor 15 minutes. The tetrahydrofuran was distilled off in vacuo, thenethyl acetate/hexane was added. The precipitate was collected byfiltration to obtain the title compound (10.9 g).

Reference Example 55 5-(aminosulfonyl)-2-chlorobenzoic acid (compoundS55)

To the compound S54 (10.9 g) in methanol (120 ml) solution, 2N sodiumhydroxide aqueous solution (40 ml) was added and the mixture was stirredat room temperature for 3 hours. The methanol was distilled off invacuo, then the remaining solution was made acidic by 6M hydrochloricacid and the precipitated solid was collected by filtration to obtainthe title compound (10 g).

Reference Example 56 Tert-butyl 5-(aminosulfonyl)-2-chlorobenzoate(compound S56)

To the compound S55 (10 g) in methylene chloride (80 ml)/tert-butylalcohol (80 ml) solution, N,N′-diisopropyl-O-tert-butylisourea (40 ml)was added and the mixture was stirred under heating and reflux for 1hour. The insoluble compound was filtered out, then the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (chloroform/ethyl acetate-6/1 to 4/1) to obtain the titlecompound (8.68 g).

NMR (DMSO-d₆): δ8.09 (1H, d, J=2.3 Hz), 7.92 (1H, dd, J=8.4, 2.3 Hz),7.78 (1H, d, J=8.4 Hz), 7.57 (2H, brs), 1.57 (9H, s)

Reference Example 57N-[5-(aminosulfonyl)-2-chlorophenyl]-2,2,2-trifluoroacetoamide (compoundS57)

A solution of 3-amino-4-chlorobenzenesulfonamide (3.1 g) andtrifluoroacetic acid anhydride (2.2 ml) in tetrahydrofuran (30 ml) wasstirred at room temperature for 4 hours. The reaction solution wasconcentrated and the residue was recrystallized from hexane-ethylacetate to obtain the title compound (3.07 g).

Reference Example 58 3-amino-4-methylbenzenesulfonamide (compound S58)

A solution of 4-methyl-3-nitrobenzenesulfonamide (2.1 g) and platinumoxide (210 mg) in methanol (50 ml) was stirred under hydrogen atmosphereat room temperature for 6 hours. The insoluble compound was filteredout, then the filtrate was concentrated. The residue was recrystallizedfrom hexane/acetone to obtain the title compound (1.23 g).

Reference Example 593-(tert-butoxycarbonyl)amino-4-methylbenzenesulfonamide (compound S59)

To the compound S58 (1.2 g) in 1,4-dioxane (50 ml) solution,di-tert-butyl-dicarbonate (1.69 g) was added and the mixture was stirredunder heating and reflux for 22 hours. The reaction solution wasconcentrated, distilled water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,dried over with anhydrous magnesium sulfate, then concentrated. Theresidue was recrystallized from hexane/ethyl acetate to obtain the titlecompound (0.84 g).

NMR (DMSO-d₆): δ8.74 (1H, s), 7.88 (1H, s), 7.45 (1H, d, J=8 Hz), 7.34(1H, d, J=8 Hz), 7.27 (2H, s), 2.25 (3H, s), 1.47 (9H, s)

MS: 309 (M+Na)⁺

Reference Example 603-(tert-butoxycarbonyl)amino-4-chlorobenzenesulfonamide (compound S60)

Instead of the starting material compound of Reference Example 58, thatis, the 4-methyl-3-nitrobenzenesulfonamide,4-chloro-3-nitrobenzenesulfonamide was used for successively the similarprocedure as in Reference Example 58 and Reference Example 59 to obtainthe title compound.

NMR (CDCl₃): δ8.78 (1H, d, J=1.9 Hz), 7.52 (1H, dd, J=8.3, 1.9 Hz), 7.47(1H, d, J=8.3 Hz), 7.11 (1H, brs), 4.91 (2H, brs), 1.54 (9H, s)

MS: 329 (M+Na)⁺

Reference Example 613-(tert-butoxycarbonyl)amino-4-methoxybenzenesulfonamide (compound S61)

Instead of the starting material compound of Reference Example 58, thatis, the 4-methyl-3-nitrobenzenesulfonamide,4-methoxy-3-nitrobenzenesulfonamide was used for successively thesimilar procedure as in Reference Example 58 and Reference Example 59 toobtain the title compound. NMR (DMSO-d₆): δ7.11 (1H, d, J=2.4 Hz), 7.05(1H, dd, J=8.5, 2.4 Hz), 6.94 (1H, d, J=8.5 Hz), 5.21 (2H, brs), 3.84(3H, s), 1.30 (9H, s)

MS: 325 (M+Na)⁺

Reference Example 62 3-(tert-butoxycarbonyl)aminobenzenesulfonamide(compound S62)

Instead of the starting material compound of Reference Example 58, thatis, 4-methyl-3-nitrobenzenesulfonamide, 3-nitrobenzenesulfonamide wasused for successively the similar procedure as in Reference Example 58and Reference Example 59 to obtain the title compound.

NMR (DMSO-d₆): δ9.67 (1H, s), 8.12 (1H, s), 7.53-7.39 (3H, m), 7.30 (2H,s), 1.48 (9H, s)

MS: 272 (M+H)⁺

Reference Example 63 4-(tert-butoxycarbonyl)aminobenzenesulfonamide(compound S63)

Instead of the starting material compound of Reference Example 58, thatis, 4-methyl-3-nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide wasused for successively the similar procedure as in Reference Example 58and Reference Example 59 to obtain the title compound.

NMR (DMSO-d₆): δ9.70 (1H, brs), 7.69 (2H, d, J=8.4 Hz), 7.58 (2H, d,J=8.4 Hz), 7.16 (2H, s), 1.48 (9H, s)

Reference Example 644-(tert-butoxycarbonyl)amino-5-chloro-2-thiophensulfonamide (compoundS64)

Instead of the starting material compound of Reference Example 58, thatis, 4-methyl-3-nitrobenzenesulfonamide,5-chloro-4-nitrothiophen-2-sulfonamide was used for successively thesimilar procedure as in Reference Example 58 and Reference Example 59 toobtain the title compound.

NMR (DMSO-d₆): δ9.30 (1H, brs), 7.80 (2H, brs), 7.68 (1H, brs), 1.46(9H, s)

Reference Example 65 4-(tert-butoxycarbonyl)aminoethylbenzenesulfonamide(compound S65)

Instead of the starting material compound in Reference Example 59, thatis, the 4-methyl-3-nitrobenzenesulfonamide,4-aminoethylbenzenesulfonamide was used for the similar procedure as inReference Example 59 to obtain the title compound.

NMR (DMSO-d₆): δ7.73 (2H, d, J=8.2 Hz), 7.37 (2H, d, J=8.2 Hz), 7.26(2H, brs), 6.90 (1H, br), 3.20-3.10 (2H, m), 2.76 (2H, t, J=7.2 Hz),1.36 (9H, s)

MS: 323 (M+Na)⁺

Reference Example 664-chloro-3-{[(ethylamino)carbonyl]amino}benzenesulfonamide (compoundS66)

To 3-amino-4-chlorobenzenesulfonamide (420 mg) in tetrahydrofuran (2 ml)solution, ethylisocyanate (180 μl) was added and the mixture was stirredunder heating and reflux for 15 hours. The reaction solution wasconcentrated, then the residue was recrystallized fromchloroform/methanol to obtain the title compound as a crude product (550mg).

NMR (DMSO-d₆): δ8.73 (1H, d, J=2.2 Hz), 8.19 (1H, brs), 7.59 (1H, d,J=8.4 Hz), 7.42-7.35 (3H, m), 7.10 (1H, t, J=5.3 Hz), 3.19-3.09 (2H, m),1.06 (3H, t, J=7.3 Hz)

Reference Example 67 Tert-butyl 2-amino-4-aminosulfonylbenzoate(compound S67)

To tert-butyl 4-aminosulfonyl-2-(benzyloxycarbonyl)aminobenzoate (5.0 g)in tetrahydrofuran solution (50 ml), 5% palladium carbon (500 mg) wasadded and the mixture was stirred under hydrogen atmosphere at roomtemperature for 1 hour. The insoluble compound was filtered out, and thefiltrate was concentrated. The residue was diluted with ethyl acetate,then the insoluble compound was again filtered out. The filtrate wasconcentrated, and the residue was recrystallized from ethylacetate/hexane to obtain the title compound (2.9 g).

NMR (DMSO-d₆): δ7.77 (1H, d, J=8.3 Hz), 7.35 (2H, s), 7.23 (1H, s), 6.93(2H, s), 6.89 (1H, d, J=8.3 Hz), 1.54 (9H, s)

Reference Example 68N-(dimethylamino)methylidene-4-{3-(dimethylamino)-2-propenoyl}benzenesulfonamide(compound S68)

To 4-aminosulfonylacetophenone (2.5 g) in 1,4-dioxane (30 ml) solution,N,N-dimethylformamide dimethylacetal (30 ml) was added and the mixturewas stirred at 90° C. for 24 hours. The precipitate was collected byfiltration and washed with ethyl acetate to obtain the title compound (3g).

Reference Example 69 4-(1H-pyrazol-3-yl)benzenesulfonamide (compoundS69)

To the compound S68 (3 g) in methanol (50 ml) solution,hydrazine-hydrate (1.6 ml) was added and the mixture was stirred underheating and reflux for 3 hours. The reaction solution was concentrated,then the residue was recrystallized from methanol/diethylether to obtainthe title compound (1.3 g).

NMR (DMSO-d₆): δ13.1 (1H, br), 7.98 (2H, d, J=8 Hz), 7.84 (2H, d, J=8Hz), 7.32 (2H, brs), 6.82 (1H, s)

Reference Example 70N-tert-butoxycarbonyl-N′-(4-chlorophenyl)-N′-methylsulfonylurea(compound S70)

To chlorosulfonylisocyanate (1.1 g) in methylene chloride (10 ml)solution, 2-methyl-2-propanol (0.75 ml) was added under ice cooling andthe mixture was stirred at that temperature for 10 hours. Triethylamine(2.2 ml) and 4-chloro-N-methylaniline (0.96 ml) were added to thereaction solution under ice cooling and the mixture was stirred at roomtemperature for 5 days. Distilled water was added to the reactionsolution, then this was extracted with chloroform. The organic layer waswashed with 1N hydrochloric acid and saturated saline, dried over withanhydrous magnesium sulfate, then concentrated. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=6/1 to 1/1) toobtain the title compound (2.2 g).

Reference Example 71 N-(4-chlorophenyl)-N-methylsulfamide (compound S71)

To the compound S70 (2.2 g), a 4M hydrochloric acid/1,4-dioxane solution(20 ml) was added and the mixture was stirred at room temperature for1.5 hours. The reaction mixture was concentrated to obtain the titlecompound (1.5 g).

Reference Example 72 N-[(1R)-1-phenylethyl]urea (compound S72)

To (1R)-1-phenylethylamine (1 g) and triethylamine (1.15 ml) intetrahydrofuran (25 ml) solution, 4-nitrophenylchlorocarbonate (1.66 g)was added at −20° C. and the mixture was stirred at room temperature for30 minutes. Further, 28% ammonia water (4 ml) was added to the reactionsolution and the mixture was stirred at room temperature for 30 minutes.The tetrahydrofuran was distilled off in vacuo, and the mixture wasextracted with ethyl acetate. The organic layer was successively washedwith 2N sodium hydroxide aqueous solution, distilled water, saturatedpotassium hydrogensulfate aqueous solution, and saturated saline anddried over with anhydrous sodium sulfate, then concentrated. The residuewas recrystallized from ethyl acetate/hexane to obtain the titlecompound (860 mg).

Reference Example 73N-benzyloxycarbonyl-(1R)-1-(1H-tetrazol-5-yl)propylamine (compound S73)

To N-benzyloxycarbonyl-(1R)-1-cyanopropylamine (85.6 mg) in suspension(3 ml), sodium azide (28 mg) and zinc bromide (88.3 mg) were added andthe mixture was stirred under heating and reflux for 24 hours. 3Nhydrochloric acid and ethyl acetate were added to the reaction solutionand the mixture was stirred until there were no longer any insolubles.The obtained solution was extracted with ethyl acetate, then the organiclayer was concentrated. 0.25N sodium hydroxide aqueous solution wasadded to the residue, the mixture was stirred for 30 minutes, and theinsoluble compound was filtered. 6N hydrochloric acid was added to thefiltrate to adjust to pH 1, then this was concentrated. The residue wasdiluted with 1N hydrochloric acid, then the solids were collected byfiltration to obtain the title compound (60.4 mg).

Reference Example 74 (1R)-1-(1H-tetrazol-5-yl)propylamine hydrochloride(compound S74)

To the compound S73 (31.6 mg) in ethanol (2 ml) solution, 10% palladiumcarbon (4.7 mg) was added and the mixture was stirred under hydrogenatmosphere at room temperature for 4 days. The insoluble compound wasfiltered out, then the filtrate was concentrated. The residue wasdiluted with 4N hydrogen chloride/ethyl acetate solution, thenconcentrated. Distilled water was added to the residue, then theobtained aqueous solution was washed with ethyl acetate, thenconcentrated to obtain the title compound (20.8 mg).

NMR (DMSO-d₆): δ8.30 (3H, brs), 4.65 (1H, t, 7.2 Hz), 2.06-1.90 (2H, m),0.81 (3H, t, 7.5 Hz)

MS: 128 (M+H)⁺

Reference Example 75 Tert-butyl 2-fluoro-5-(1-nitropropyl)benzoate(compound S75)

To tert-butyl 5-bromo-2-fluorobenzoate (1.26 g) in dimethoxyethane (22.9ml) solution, tris(dibenzylideneacetone)dipalladium (0.10 g),2-(di-tert-butylphosphino)-2′-methylbiphenyl (0.14 g), tripotassiumphosphate (1.07 g), and 1-nitropropane (0.82 ml) were added, the mixturewas stirred at room temperature for 1 minute, then the mixture wasstirred under heating and reflux for 15 hours. The insoluble compoundwas filtered out, then the filtrate was concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate,ethyl acetate: 0 to 10%) to obtain the title compound (392 mg).

Reference Example 76 tert-butyl2-fluoro-5-(N-hydroxypropanimidoyl)benzoate (compound S76)

To the compound S75 (392 mg) in 1,4-dioxane (15 ml)/distilled water (1ml) solution, potassium tert-butoxide (202 mg) was added and the mixturewas stirred at room temperature for 45 hours. 1N hydrochloric acid wasadded to the reaction solution under ice cooling, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. Sodium acetate (255 mg) and hydroxylamine hydrochloride(159 mg) were added to the residue in ethanol (10 ml) solution, then themixture was stirred under heating and reflux for 55 hours. The reactionsolution was concentrated, then the residue was diluted with ethylacetate. The obtained solution was successively washed with distilledwater and saturated saline, dried over with anhydrous sodium sulfate,then concentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate, ethyl acetate: 10 to 30%) toobtain the title compound (413 mg).

Reference Example 77 tert-butyl 5-(1-aminopropyl)-2-fluorobenzoatehydrochloride (compound S77)

A suspension of the compound S76 (413 mg) and 10% palladium carbon (124mg) in ethanol (20 ml) was stirred at a 4 atm hydrogen atmosphere andthe mixture was stirred at room temperature for 7 hours. The insolublecompound was filtered out, then the filtrate was concentrated. Theresidue was diluted with ethyl acetate, 4N hydrogen chloride/ethylacetate solution (0.39 ml) was added, and the precipitate was collectedby filtration to obtain the title compound (244 mg).

NMR (DMSO-d₆): δ8.41 (3H, br), 7.91 (1H, dd, 6.8, 2.2 Hz), 7.74-7.69(1H, m), 7.35 (1H, dd, 10.5, 8.6 Hz), 4.20 (1H, dd, 9.0, 5.6 Hz),1.99-1.85 (1H, m), 1.82-1.70 (1H, m), 1.51 (9H, s), 0.72 (3H, t, 7.4 Hz)

MS: 237 (M−NH₂)⁺

Reference Example 78 Tert-butyl 4-(1-aminopropyl)-2-hydroxybenzoate(compound S78)

Instead of the starting material compound of Reference Example 75, thatis tert-butyl 5-bromo-2-fluorobenzoate, tert-butyl4-bromo-2-hydroxybenzoate was used for successively the similarprocedure as in Reference Example 75 to Reference Example 77 to obtainthe title compound.

NMR (DMSO-d₆): δ7.69 (1H, d, J=8.2 Hz), 6.97 (1H, d, J=1.4 Hz), 6.92(1H, dd, J=8.2, 1.4 Hz), 3.82 (1H, t, J=6.8 Hz), 3.31 (2H, br),1.71-1.54 (2H, m), 1.57 (9H, s), 0.76 (3H, t, J=7.4 Hz)

MS: 235 (M−NH₂)⁺

Reference Example 79 Tert-butyl 5-(1-aminopropyl)-2-aminobenzoatedihydrochloride (compound S79)

Instead of the starting material compound of Reference Example 75, thatis, tert-butyl 5-bromo-2-fluorobenzoate, tert-butyl5-chloro-2-nitrobenzoate was used for successively the similar procedureas in Reference Example 75 to Reference Example 77 to obtain the titlecompound.

NMR (DMSO-d₆): δ8.22 (3H, brs), 7.67 (1H, d, 1.2 Hz), 7.30 (1H, dd, 8.6,1.2 Hz), 6.76 (1H, d, 8.6 Hz), 5.50-4.40 (3H, br), 3.95-3.86 (1H, m),1.94-1.83 (1H, m), 1.79-1.65 (1H, m), 1.51 (9H, s), 0.72 (3H, t, 7.4 Hz)

MS: 234 (M−NH₂)⁺

Reference Example 80 tert-butyl 4-(1-aminopropyl)-2-aminobenzoate(compound S80)

Instead of the starting material compound of Reference Example 75, thatis, tert-butyl 5-bromo-2-fluorobenzoate, tert-butyl2-amino-4-chlorobenzoate was used for successively the similar procedureas in Reference Example 75 to Reference Example 77 to obtain the titlecompound.

NMR (CDCl₃): δ7.44 (1H, d, 8.3 Hz), 6.58 (1H, d, 1.6 Hz), 6.54 (1H, dd,8.3, 1.6 Hz), 5.66 (2H, brs), 3.68 (1H, t, 6.7 Hz), 1.68-1.59 (2H, m),1.56 (9H, s), 0.85 (3H, t, 7.3 Hz)

MS: 234 (M−NH₂)⁺

Reference Example 81 tert-butyl4-(1-aminopropyl)-2-fluorobenzoatehydrochloride (compound S81)

Instead of the starting material compound of Reference Example 75, thatis, tert-butyl 5-bromo-2-fluorobenzoate, tert-butyl4-bromo-2-fluorobenzoate was used for successively the similar procedureas in Reference Example 75 to Reference Example 77 to obtain the titlecompound.

NMR (DMSO-d₆): δ8.50 (3H, br), 7.83 (1H, t, 7.9 Hz), 7.48-7.44 (1H, m),7.37 (1H, dd, 7.9, 1.4 Hz), 4.21 (1H, dd, 8.8, 5.7 Hz), 1.99-1.85 (1H,m), 1.83-1.71 (1H, m), 1.51 (9H, s), 0.73 (3H, t, 7.4 Hz)

MS: 237 (M−NH₂)⁺

Reference Example 82 tert-butyl 3-[(1S)-1-hydroxypropyl]benzoate(compound S82)

To the (1S,2R)-2-di-n-butylamino-1-phenyl-1-propanol (200 mg) in toluene(7 ml) solution, tert-butyl 3-formylbenzoate (3 g) in hexane (7 ml)solution was added and the mixture was stirred at room temperature for20 minutes. Next, diethylzinc in 1N hexane solution (33 ml) was added tothe reaction solution under ice cooling and the mixture was stirred atthat temperature for 18 hours. Saturated ammonium chloride aqueoussolution was added to the reaction solution, the mixture was stirred at20 minutes, and 1N hydrochloric acid was added. The obtained mixedsolution was extracted with ethyl acetate. The organic layer was driedover with anhydrous sodium sulfate, then concentrated to obtain thetitle compound (3.5 g).

Reference Example 83 tert-butyl 3-[(1R)-1-aminopropyl]benzoateL-tartrate (compound S83)

To the compound S82 (4.5 g) in tetrahydrofuran (100 ml) solution,phthalimide (3.4 g), triphenylphosphine (6 g), anddiethylazodicarboxylate (40% toluene solution) (10 g) were added and themixture was stirred at room temperature for 4 hours. The reactionsolution was concentrated, and the residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=5/1). To the obtainedcompound (3.5 g) in methanol (25 ml) solution, hydrazine hydrate (1.6ml) was added and the mixture was stirred under heating and reflux for 2hours. The precipitate of the reaction solution was filtered out, andthe filtrate was concentrated. The residue was diluted with ethylacetate and was successively washed with distilled water and saturatedsaline. The organic layer was dried over with anhydrous sodium sulfate,then concentrated. The residue was diluted with methanol, L-tartaricacid (1.34 g) was added, then the mixture was concentrated. The obtainedresidue was recrystallized from ethyl acetate/ethanol to obtain thetitle compound (2.01 g).

NMR (DMSO-d₆): δ8.05 (1H, s), 8.01 (1H, d, J=7.7 Hz), 7.65 (1H, d, J=7.7Hz), 7.57 (1H, t, J=7.7 Hz), 4.84 (3H, br), 4.26 (1H, dd, J=9.1, 6.0Hz), 2.12-1.92 (2H, m), 1.61 (9H, s), 0.90 (3H, t, J=7.3 Hz)

MS: 219 (M−NH₂)⁺

Reference Example 84 tert-butyl 3-[(1S)-1-aminopropyl]benzoateD-tartrate (compound S84)

To tert-butyl 3-formylbenzoate (2.9 g) and R-(+)-phenyl lactic acid (1g) in methylene chloride (30 ml) solution, titanium tetraisopropoxide(5.8 ml) and diethylzinc in 1M hexane solution (42 ml) were added underice cooling and the mixture was stirred at room temperature for 16hours. 1N hydrochloric acid was added to the reaction solution under icecooling and the precipitated compound was filtered out. The filtrate wasextracted with ethyl acetate. The organic layer was successively washedwith saturated sodium hydrogencarbonate aqueous solution, distilledwater, saturated potassium hydrogensulfate aqueous solution, andsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The obtained compound (3.07 g) was used instead of thestarting material of Reference Example 83, that is, the compound S82,while D-tartaric acid was used instead of L-tartaric acid for thesimilar procedure as in Reference Example 83 to obtain the titlecompound.

Reference Example 85 tert-butyl5-[(1R)-1-aminopropyl]-2-furancarboxylate D-tartrate (compound S85)

Instead of the starting material compound of Reference Example 82, thatis, the tert-butyl 3-formylbenzoate, tert-butyl5-formyl-2-furancarboxylate was used for the similar procedure as inReference Example 82, while D-tartaric acid was used instead ofL-tartaric acid for the similar procedure as in Reference Example 83 toobtain the title compound.

NMR (DMSO-d₆): δ8.25-7.30 (3H, br), 7.16 (1H, d, J=3.5 Hz), 6.59 (1H, d,J=3.5 Hz), 4.15 (1H, t, J=6.8 Hz), 3.95 (2H, s), 1.89-1.70 (2H, m), 1.51(9H, s), 0.85 (3H, dt, J=7.3, 2.3 Hz)

MS: 226 (M+H)⁺

Reference Example 86 tert-butyl 4-(1-aminopropyl)benzoate hydrochloride(compound S86)

To copper (I) iodide (3.1 g) in diethylether (70 ml) suspension,ethylmagnesium bromide (0.89M tetrahydrofuran solution) (35 ml) wasadded at −23° C. and the mixture was stirred at that temperature for 20minutes. Next, tert-butyl 4-formylbenzoate (3 g) in diethylether (10 ml)solution was added to the reaction solution and the mixture was stirredat −23° C. for 30 minutes. Saturated ammonium chloride aqueous solutionand 28% ammonia water were added to the reaction solution, the mixturewas stirred at room temperature for 40 minutes, and the mixture wasextracted with ethyl acetate. The organic layer was successively washedwith distilled water and saturated saline, dried over with anhydroussodium sulfate, then concentrated. The obtained compound (3.7 g) wasused as an starting material instead of the starting material ofReference Example 83, that is, the compound S82, while 4N hydrochloricacid/ethyl acetate was used instead of L-tartaric acid for the similarprocedure as in Reference Example 83 to obtain the title compound.

NMR (DMSO-d₆): δ8.04 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz), 4.84(3H, br), 4.25 (1H, dd, J=9, 6 Hz), 2.10-1.90 (2H, m), 1.60 (9H, s),0.90 (3H, t, J=7.4 Hz)

MS: 219 (M−NH₂)⁺

Reference Example 87 tert-butyl 3-(1-aminopropyl)benzoate hydrochloride(compound S87)

Instead of the starting material compound of Reference Example 86, thatis, tert-butyl 4-formylbenzoate, tert-butyl 3-formylbenzoate was usedfor the similar procedure as in Reference Example 86 to obtain the titlecompound.

NMR (DMSO-d₆): δ8.05 (1H, s), 8.01 (1H, d, J=7.7 Hz), 7.65 (1H, d, J=7.7Hz), 7.57 (1H, t, J=7.7 Hz), 4.84 (3H, br), 4.26 (1H, dd, J=9.1, 6.0Hz), 2.12-1.92 (2H, m), 1.61 (9H, s), 0.90 (3H, t, J=7.3 Hz)

MS: 219 (M−NH₂)⁺

Reference Example 88 tert-butyl 3-(1-aminopropyl)-2-benzyloxybenzoatehydrochloride (compound S88)

Instead of the starting material compound of Reference Example 86, thatis, tert-butyl 4-formylbenzoate, tert-butyl 2-benzyloxy-3-formylbenzoatewas used for the similar procedure as in Reference Example 86 to obtainthe title compound.

MS: 364 (M+Na)⁺

Reference Example 89 tert-butyl 5-(1-aminopropyl)-2-benzyloxybenzoatehydrochloride (compound S89)

Instead of the starting material compound of Reference Example 86, thatis tert-butyl 4-formylbenzoate, tert-butyl 2-benzyloxy-5-formylbenzoatewas used for the similar procedure as in Reference Example 86 to obtainthe title compound.

NMR (DMSO-d₆): δ7.66 (1H, d, J=2.5 Hz), 7.51-7.47 (3H, m), 7.39-7.30(3H, m), 7.22 (1H, d, J=8.7 Hz), 5.19 (2H, s), 4.82 (3H, s), 4.14 (1H,dd, J=9.3, 5.9 Hz), 2.09-1.88 (2H, m), 1.50 (9H, s), 0.89 (3H, t, J=7.3Hz)

MS: 364 (M+Na)⁺

Reference Example 90 tert-butyl 5-(1-aminopropyl)-2-thiophencarboxylatehydrochloride (compound S90)

Instead of the starting material compound of Reference Example 86, thatis, tert-butyl 4-formylbenzoate, tert-butyl 5-formylthiophencarboxylatewas used for the similar procedure as in Reference Example 86 to obtainthe title compound.

NMR (DMSO-d₆): δ8.67-8.43 (2H, br), 7.64 (1H, d, J=3.7 Hz), 7.28 (1H, d,J=3.7 Hz), 4.55-4.45 (1H, br), 2.04-1.77 (2H, m), 1.49 (9H, s), 0.80(3H, t, J=7.4 Hz)

MS: 242 (M+H)⁺

Reference Example 91 tert-butyl 5-(1-aminopropyl)-2-furancarboxylatehydrochloride (compound S91)

Instead of the starting material compound of Reference Example 86, thatis, tert-butyl 4-formylbenzoate, tert-butyl 5-formylfurancarboxylate wasused for the similar procedure as in Reference Example 86 to obtain thetitle compound.

NMR (DMSO-d₆): δ8.67-8.43 (2H, br), 7.17 (1H, d, J=3.5 Hz), 6.71 (1H, d,J=3.5 Hz), 4.41-4.31 (1H, br), 1.95-1.83 (2H, m), 1.49 (9H, s), 0.82(3H, t, J=7.4 Hz)

MS: 226 (M+H)⁺

Reference Example 92 tert-butyl 6-(1-aminopropyl)-2-pyridinecarboxylatedihydrochloride (compound S92)

Instead of the starting material compound of Reference Example 86, thatis, tert-butyl 4-formylbenzoate, tert-butyl 6-formylpicolinate was usedfor the similar procedure as in Reference Example 86 to obtain the titlecompound.

NMR (CDCl₃): δ9.12-8.90 (3H, br), 7.96 (1H, d, J=7.7 Hz), 7.84 (1H, t,J=7.7 Hz), 7.57 (1H, d, J=7.7 Hz), 4.67-4.59 (1H, br), 2.40-2.25 (1H,m), 2.15-2.02 (1H, m), 1.59 (9H, s), 0.92 (3H, t, J=7.4 Hz)

MS: 237 (M+H)⁺

Reference Example 93 tert-butyl 5-(1-aminopropyl)-nicotinatedihydrochloride (compound S93)

Instead of the starting material compound of Reference Example 86, thatis, tert-butyl 4-formylbenzoate, tert-butyl 5-formyl nicotinate was usedfor the similar procedure as in Reference Example 86 to obtain the titlecompound.

NMR (DMSO-d₆): δ9.01 (1H, d, J=2.0 Hz), 8.87 (1H, d, J=2.2 Hz),8.85-8.65 (3H, br), 8.42 (1H, brs), 4.41-4.32 (1H, br), 2.10-1.96 (1H,m), 1.92-1.79 (1H, m), 1.55 (9H, s), 0.75 (3H, t, J=7.4 Hz)

MS: 237 (M+H)⁺

Reference Example 94 1-(3-tert-butoxyisoxazol-5-yl)propylamine (compoundS94)

Instead of the starting material compound of Reference Example 86, thatis, tert-butyl 4-formylbenzoate, 3-tert-butoxy-5-isoxazole carboaldehydewas used for the similar procedure as in Reference Example 86 to obtainthe title compound.

NMR (CDCl₃): δ5.65 (1H, s), 3.84 (1H, t, 6.6 Hz), 1.86-1.66 (2H, m),1.52 (9H, s), 0.96 (3H, t, 7.5 Hz)

MS: 199 (M+H)⁺

Reference Example 95 1-(4-bromo-3-nitrophenyl)-1-propanone (compoundS95)

To fuming nitric acid (200 ml), 1-(4-bromophenyl)-1-propanone (40 g) wasadded while keeping the inside temperature of the mixture at 5 to 10° C.The reaction solution was stirred at that temperature for 30 minutes andthen poured into ice. The precipitate was collected by filtration,washed with distilled water, and recrystallized from methanol to obtainthe title compound (18 g).

NMR (CDCl₃): δ8.38 (1H, d, J=2.0 Hz), 7.99 (1H, dd, J=8.2, 2.0 Hz), 7.86(1H, d, J=8.2 Hz), 3.01 (2H, q, J=7.1 Hz), 1.25 (3H, t, J=7.1 Hz)

Reference Example 96 2-nitro-4-propionylbenzonitrile (compound S96)

To the compound S95 (100 g) in N,N-dimethylformamide (200 ml) solution,copper cyanide (34.7 g) was added and stirred at 100° C. for 1 hour.Iron (III) chloride (180 g) in concentrated hydrochloric acid (45ml)/distilled water (270 ml) solution was added to the reactionsolution, the mixture was stirred at 70° C. for 30 minutes, then thiswas extracted with a hexane/ethyl acetate=1/2 mixed solvent. The organiclayer was successively washed with 1N hydrochloric acid, 1N sodiumhydroxide aqueous solution, and saturated saline, was filtered by acolumn packed with anhydrous sodium sulfate and silica gel, and thefiltrate was concentrated. Methonal was added to the residue, then themixture was ice-cooled. The precipitated solid was collected byfiltration to obtain the title compound (33 g).

NMR (CDCl₃): δ8.84 (1H, d, J=1.6 Hz), 8.35 (1H, dd, J=7.9, 1.6 Hz), 8.04(1H, d, J=7.9 Hz), 3.09 (2H, q, J=7.1 Hz), 1.29 (3H, t, J=7.1 Hz)

Reference Example 97 2-nitro-4-propionylbenzoic acid (compound S97)

A reaction mixture of the compound S96 (168 g), concentrated sulfuricacid (462 ml), and distilled water (378 ml) was stirred at 110° C. for12 hours. The reaction solution was poured into ice water, then themixture was extracted with ethyl acetate. The organic layer wasextracted with 2N sodium hydroxide aqueous solution. The aqueous layerwas neutralized by hydrochloric acid and the mixture was extracted withethyl acetate. The organic layer was successively washed with saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated. Theresidue was dried in vacuo to obtain the title compound (159 g).

NMR (CDCl₃): δ8.43 (1H, s), 8.3 (1H, d, J=7.9 Hz), 7.98 (1H, d, J=7.9Hz), 3.14 (2H, q, J=7.0 Hz), 1.09 (3H, t, J=7.0 Hz)

Reference Example 98 tert-butyl 2-nitro-4-propionylbenzoate (compoundS98)

To magnesium sulfate (227 g) in methylene chloride (840 ml) suspension,concentrated sulfuric acid (20 ml) was added and the mixture was stirredat room temperature for 15 minutes. Next, the compound S97 (84 g) andtert-butyl alcohol (219 ml) were successively added to the mixture andthe mixture was stirred at room temperature for 4 days. Silica gel wasadded to the reaction solution which was then filtered. The filtrate wasconcentrated, hexane was added to the residue, and the precipitatedsolid was collected by filtration to obtain the title compound (92 g).

NMR (CDCl₃): δ8.41 (1H, d, J=1.5 Hz), 8.2 (1H, dd, J=7.9, 1.5 Hz), 7.8(1H, d, J=−7.9 Hz), 3.04 (2H, q, J=7.2 Hz), 1.58 (9H, s), 1.26 (3H, t,J=7.2 Hz)

Reference Example 99 tert-butyl 4-[(1S)-1-hydroxypropyl]-2-nitrobenzoate(compound S99)

To the compound S98 (139 g) in tetrahydrofuran (695 ml) solution,(−)-B-chlorodiisopinocampheylborane was added dropwise under icecooling, then the mixture was stirred at that temperature for 2 hours.The reaction solution was concentrated, and the residue was diluted withdiethylether (21). Diethanol amine (145 ml) was added to the obtainedsolution under ice cooling and the mixture was stirred at roomtemperature for 2 hours. The precipitate was filtered out, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=10/1 to 4/1) to obtain the titlecompound (109 g).

NMR (CDCl₃): δ7.81 (1H, s), 7.71 (1H, d, J=7.9 Hz), 7.6 (1H, d, J=7.9Hz), 4.79-4.70 (1H, m), 1.85-1.75 (2H, m), 1.56 (9H, s), 1.00-0.90 (3H,m)

Reference Example 100 tert-butyl 4-[(1R)-1-azide propyl]-2-nitrobenzoate(compound S100)

To the compound S99 (109 g) in tetrahydrofuran (436 ml) solution,triethylamine (108 ml) and methanesulfonyl chloride (36 ml) were addedunder ice cooling and the mixture was stirred for 15 minutes. Distilledwater was added to the reaction solution, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,dried over with anhydrous sodium sulfate, then concentrated. To the thusobtained tert-butyl4-[(1S)-1-[(methylsulfonyl)oxy]propyl-2-nitrobenzoate (137 g) inN,N-dimethylformamide (685 ml) solution, sodium azide (16.3 g) was addedunder ice cooling and the mixture was stirred at room temperature for 1hour. Distilled water was added to the reaction solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was dried in vacuo to obtain the titlecompound (139 g).

NMR (CDCl₃): δ8.01 (1H, s), 7.74 (1H, d, J=8.1 Hz), 7.56 (1H, d, J=8.1Hz), 4.5 (1H, t, J=7 Hz), 1.93-1.78 (2H, m), 1.56 (9H, s), 0.96 (3H, t,J=7.3 Hz)

Reference Example 101 tert-butyl 4-[(1R)-1-aminopropyl]-2-nitrobenzoatehydrochloride (compound S101)

To the compound S100 (139 g) in tetrahydrofuran (1.41) solution,distilled water (70 ml) and triphenylphosphine (119 g) were added underice cooling and the mixture was stirred at 50° C. for 20 hours. Thereaction solution was concentrated, toluene and 0.5N hydrochloric acidwere added, and the aqueous layer and the organic layer were separated.Hexane was added to the organic layer, and the mixture was extractedwith 0.5N hydrochloric acid. A sodium hydroxide aqueous solution wasadded to the combined aqueous layer, then the obtained alkali aqueoussolution was extracted with ethyl acetate. The organic layer was washedwith saturated saline, dried over with anhydrous sodium sulfate, andconcentrated to obtain tert-butyl4-[(1R)-1-aminopropyl]-2-nitrobenzoate. The obtained tert-butyl4-[(1R)-1-aminopropyl]-2-nitrobenzoate was diluted with ethyl acetate,4N hydrogen chloride/ethyl acetate (110 ml) was added, and theprecipitate was collected by filtration. The filtrate was recrystallizedfrom N,N-dimethylformamide/ethyl acetate to obtain the title compound(45.8 g).

NMR (DMSO-d₆): δ8.66 (3H, br), 8.22 (1H, s), 7.96-7.89 (2H, m), 4.38(1H, dd, 8.9, 5.8 Hz), 2.04-1.93 (1H, m), 1.92-1.80 (1H, m), 1.50 (9H,s), 0.77 (3H, t, 7.4 Hz)

MS: 281 (M+H)⁺

Reference Example 102 tert-butyl 2-amino-4-[(1R)-1-aminopropyl]benzoateD-tartrate (compound S102)

The tert-butyl 4-[(1R)-1-aminopropyl]-2-nitrobenzoate (4.66 g) obtainedat the step of Reference Example 101 was dissolved in ethanol (150 ml),10% palladium carbon (1 g) was added, and the mixture was stirred underhydrogen atmosphere at room temperature for 8 hours. The insolublecompound was filtered out, and the filtrate was concentrated. Ethanolwas added to the residue and the mixture was stirred under heating andreflux until dissolving. Next, ethyl acetate was added, the mixture wascooled to room temperature, and the precipitated crystal was collectedby filtration to obtain the title compound (5.42 g).

NMR (CDCl₃): δ7.67 (1H, d, J=8.2 Hz), 6.73 (1H, d, J=1.4 Hz), 6.67 (2H,s), 6.58 (1H, dd, J=8.2, 1.4 Hz), 3.96-3.89 (1H, m), 3.85 (2H, s),1.92-1.64 (2H, m), 1.52 (9H, s), 0.76 (3H, t, J=7.4 Hz)

MS: 234 (M−NH₂)⁺

Reference Example 103 tert-butyl 5-[(1R)-1-aminopropyl]-nicotinateD-tartrate (compound S103)

Instead of the starting material of Reference Example 56, that is, thecompound S55, the 5-bromonicotinic acid was used for the similarprocedure as in Reference Example 56. To the obtained tert-butyl5-bromonicotinate (22.4 g), dimethylacetoamide (112 ml),tris(dibenzylideneacetone)dipalladium (1.59 g), zinc cyanide (6.1 g),diphenylphosphinoferrocene (1.92 g), and zinc powder (0.68 g) were addedand the mixture was stirred under argon atmosphere at 120° C. for 1.5hours. The reaction solution was filtered by sellite, which was thenwashed with ethyl acetate, and the filtrate was washed with saturatedsaline. The organic layer was dried over with anhydrous sodium sulfate,then concentrated. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=3/1) to obtain tert-butyl5-cyanonicotinate (13.1 g).

To copper (I) iodide (1.0 g) in tetrahydrofuran (18 ml) suspension,ethylmagnesium bromide (0.86M tetrahydrofuran solution (12.3 ml) wasadded under cooling at −20° C., the mixture was stirred at 0° C. for 30minutes, then the tert-butyl 5-cyanonicotinate (0.9 g) obtained above intetrahydrofuran (9 ml) solution was added at the similar temperature.After stirring for 1 hour, saturated ammonium chloride aqueous solutionand ethyl acetate were added to the mixture and the solution separated.The aqueous layer was extracted with ethyl acetate, while the combinedorganic layer was washed with saturated saline, then was dried over withanhydrous sodium sulfate and concentrated. The obtained residue waspurified by silica gel column chromatography (hexane/ethyl acetate=3/1).The obtained tert-butyl 5-propionylnicotinate was used successivelyinstead of the starting material compound of Reference Example 99, thatis, the compound S98, for the similar procedure as in Reference Example99 and Reference Example 100, then D-tartaric acid was used instead ofthe 4N hydrogen chloride/ethyl acetate used as the reagent in ReferenceExample 101 for the similar procedure as in Reference Example 101 toobtain the title compound.

NMR (DMSO-d₆): δ8.99 (1H, d, J=2.0 Hz), 8.81 (1H, d, J=2.1 Hz), 8.33(1H, t, J=2.0 Hz), 7.75-6.95 (3H, br), 4.31 (0.5H, d, J=2.6 Hz), 4.18(1H, t, J=6.4 Hz), 4.04-3.99 (0.5H, br), 3.86 (1H, s), 1.95-1.71 (2H,m), 1.57 (9H, s), 0.78 (3H, t, J=7.4 Hz)

MS: 237 (M+H)⁺

Reference Example 104 tert-butyl5-[(1R)-1-aminopropyl]-3-furancarboxylate D-tartrate (compound S104)

To 3-furancarboxylic acid (1.12 g), nitromethane (10 ml), indium (III)trifluoromethane sulfonate (56 mg), lithium perchlorate (1.06 g), andpropionic anhydride (1.28 ml) were added and the mixture was stirred at50° C. for 3 hours. Water was added to the reaction solution and thesolution separated. The aqueous layer was extracted with ethyl acetate.The combined organic layer was washed with saturated saline, dried overwith anhydrous sodium sulfate, and concentrated. The obtained5-propionyl-3-furancarboxylic acid was used instead of the startingmaterial of Reference Example 56, that is, the compound S55, for thesimilar procedure as in Reference Example 56 to obtain tert-butyl5-propionyl-3-furancarboxylate. This was used instead of the startingmaterial compound of Reference Example 99, that is, the compound S98,for the similar procedure as in Reference Example 99 and ReferenceExample 100, then D-tartaric acid was used successively instead of the4N hydrogen chloride/ethyl acetate used as the reagent in ReferenceExample 101 for the similar procedure as in Reference Example 101 toobtain the title compound.

NMR (DMSO-d₆): δ8.28 (1H, s), 6.65 (1H, s), 4.12 (1H, t, J=6.3 Hz), 3.91(2H, s), 1.89-1.72 (2H, m), 1.50 (9H, s), 0.82 (3H, t, J=7.4 Hz)

MS: 209 (M−NH₂)³⁰

Reference Example 105 tert-butyl 2-[(1R)-1-aminopropyl]-isonicotinateD-tartrate (compound S105)

Instead of the starting material compound of Reference Example 103, thatis, 5-bromonicotinic acid, 2-chloroisonicotinic acid was used for thesimilar procedure as in Reference Example 103 to obtain the titlecompound.

NMR (DMSO-d₆): δ8.81 (1H, d, J=4.9 Hz), 7.90 (1H, d. J=1.5 Hz), 7.77(1H, dd, J=4.9, 1.5 Hz), 4.39 (1H, t, J=6.8 Hz), 3.83 (2H, s), 1.90-1.76(2H, m), 1.57 (9H, s), 0.80 (3H, t, J=7.5 Hz)

MS: 237 (M+H)⁺

Reference Example 106 tert-butyl 6-[(1R)-1-aminopropyl]-nicotinateD-tartrate (compound S106)

Instead of the starting material compound of Reference Example 103, thatis, 5-bromonicotinic acid, 6-chloronicotinic acid was used for thesimilar procedure as in Reference Example 103 to obtain the titlecompound.

NMR (DMSO-d₆): δ9.04 (1H, d, J=2.1 Hz), 8.29 (1H, dd. J=8.1, 2.1 Hz),7.62 (1H, d, J=8.1 Hz), 4.34 (1H, t, J=6.8 Hz), 3.84 (2H, s), 1.90-1.74(2H, m), 1.57 (9H, s), 0.79 (3H, t, J=7.5 Hz)

MS: 237 (M+H)⁺

Reference Example 107 tert-butyl5-[(1S)-1-hydroxypropyl]-thiophen-3-carboxylate (compound S107)

Instead of the starting material compound of Reference Example 104, thatis, 3-furan carboxylic acid, 3-thiophencarboxylic acid was used for thesimilar procedure as in Reference Example 104 to obtain tert-butyl5-propionyl-3-thiophencarboxylate.

To(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole(1M toluene solution) (21 μl) in toluene (0.21 ml) solution, aboranedimethylaniline complex (74 μl) was added under ice cooling, thenthe tert-butyl 5-propionyl-thiophen-2-carboxylate (100 mg) obtained bythe above procedure in tetrahydrofuran (0.5 ml) solution was addeddropwise and the mixture was stirred at that temperature for 1 hour.Methanol was added to the reaction solution, the mixture was stirred for10 minutes, then 1N hydrochloric acid was added and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1) to obtain the title compound(97.8 mg).

Reference Example 108 tert-butyl5-[(1R)-1-aminopropyl]-thiophen-3-carboxylate D-tartrate (compound S108)

Instead of the starting material of Reference Example 100, that is, thecompound S99, the compound S107 was used for the similar procedure aswith Reference Example 100, then further, instead of the 4N hydrogenchloride/ethyl acetate used as the reagent in Reference Example 101,D-tartaric acid was used for the similar procedure as in ReferenceExample 101 to obtain the title compound.

NMR (DMSO-d₆): δ8.17 (1H, s), 7.41 (1H, s), 4.35 (1H, t, J=7.8 Hz), 3.93(2H, s), 1.92-1.70 (2H, m), 1.51 (9H, s), 0.84 (3H, t, J=7.3 Hz)

MS: 225 (M+H)⁺

Reference Example 109 4-(1-aminopropyl)aniline hydrochloride (compoundS109)

To 1-(4-aminophenyl)propan-1-on oxime (2.75 g) in ethanol (60 ml)solution, 10% palladium carbon (280 mg) was added, then the mixture wasstirred under 4 to 5 atm hydrogen atmosphere at room temperature for 16hours. The insoluble compound was filtered out, then a 4N hydrogenchloride/1,4-dioxane solution (6 ml) was added to the filtrate. Theethanol was distilled off in vacuo, then the precipitate was collectedby filtration to obtain the title compound (1.2 g).

NMR (DMSO-d₆): δ8.55 (3H, brs), 7.51 (2H, d, J=8.3 Hz), 7.27 (2H, d,J=8.3 Hz), 4.12-4.01 (1H, m), 2.00-1.89 (1H, m), 1.84-1.70 (1H, m), 0.71(3H, t, J=7.4 Hz)

MS: 134 (M−NH₂)⁺

Reference Example 110 1-(3-aminosulfonylphenyl)propylamine hydrochloride(compound S110)

To 3-aminosulfonylbenzoic acid (4.0 g), N,N-dimethylformamide (53 ml),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.8 g),1-hydroxybenzotriazole (2.7 g), N,O-dimethylhydroxylamine hydrochloride(1.9 g), and triethylamine (2.8 ml) were added under ice cooling and themixture was stirred at room temperature for 12 hours. A potassiumhydrogensulfate aqueous solution and ethyl acetate were added to thereaction solution and the mixture was separated. The aqueous layer wasextracted with ethyl acetate. The combined organic layer wassuccessively washed with distilled water, saturated sodiumhydrogencarbonate aqueous solution, and saturated saline, dried overwith anhydrous sodium sulfate, then concentrated. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=1/2). To the obtainedN-methoxy-N-methyl-3-aminosulfonylbenzamide (1.8 g), tetrahydrofuran (36ml) and ethyl magnesium bromide (0.89M tetrahydrofuran solution, 41 ml)were added under ice cooling, the mixture was stirred at roomtemperature for 3 hours, then saturated ammonium chloride aqueoussolution and ethyl acetate were added to reaction solution, the mixturewas separated, then organic layer was successively washed with saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated. Theobtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1). To the obtained3-propionylbenzenesulfonamide (0.97 g), ethanol (2.5 ml), sodium acetate(0.56 g), and hydroxylamine hydrochloride (0.35 g) were added and themixture was stirred at 90° C. for 3 hours. Ethyl acetate and water wereadded to the reaction solution, the mixture was separated, then theorganic layer was successively washed with saturated saline, dried overwith anhydrous sodium sulfate, then concentrated. The obtained3-(N-hydroxypropanimidoyl)benzenesulfonamide was used instead of thestarting material compound of Reference Example 109, that is,1-(4-aminophenyl)propan-1-on oxime, for the similar procedure as withReference Example 109 to obtain the title compound.

NMR (DMSO-d₆): δ8.50-8.36 (3H, br), 7.92 (1H, s), 7.83 (1H, d, J=7.5Hz), 7.71-7.60 (2H, m), 7.42 (2H, s), 4.33-4.21 (1H, br), 2.00-1.70 (2H,m), 0.75 (3H, t, J=7.4 Hz)

MS: 215 (M+H)⁺

Reference Example 111 1-(4-aminosulfonylphenyl)propylamine hydrochloride(compound S111)

Instead of the starting material compound of Reference Example 110, thatis, 3-aminosulfonylbenzoic acid, 4-aminosulfonylbenzoic acid was usedfor the similar procedure as with Reference Example 110 to obtain thetitle compound.

NMR (DMSO-d₆): δ8.60-8.45 (3H, br), 7.85 (2H, d, J=8.2 Hz), 7.63 (2H, d,J=8.2 Hz), 7.39 (2H, s), 4.29-4.20 (1H, br), 2.03-1.74 (2H, m), 0.74(3H, t, J=7.4 Hz)

MS: 215 (M+H)⁺

Reference Example 112 1-(3-methane sulfonylphenyl)propylaminehydrochloride (compound S112)

To 1-(3-methane sulfonylphenyl)propan-1-one (188 g), ethanol (4.7 ml),sodium acetate (1.09 g), and hydroxylamine hydrochloride (0.68 g) wereadded and the mixture was stirred at 90° C. for 3 hours. Ethyl acetateand water were added to the reaction solution, the mixture wasseparated, then the organic layer was successively washed with saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated. Theobtained 1-(3-methane sulfonylphenyl)propan-1-one oxime was used insteadof the starting material compound 1-(4-aminophenyl)propan-1-on oxime ofReference Example 109 for the similar procedure as with ReferenceExample 109 to obtain the title compound.

NMR (DMSO-d₆): δ8.55-8.35 (2H, br), 8.06 (1H, s), 7.94 (1H, d, J=7.6Hz), 7.80 (1H, brd, J=8.3 Hz), 7.71 (1H, t, J=7.6 Hz), 4.38-4.29 (1H,br), 3.22 (3H, s), 2.03-1.78 (2H, m), 0.76 (3H, t, J=7.3 Hz)

MS: 214 (M+H)⁺

Reference Example 113 1-(4-methane sulfonylphenyl)propylaminehydrochloride (compound S113)

Instead of the starting material compound of Reference Example 112, thatis, 1-(3-methane sulfonylphenyl)propan-1-on, 1-(4-methanesulfonylphenyl)propan-1-on was used for the similar procedure as inReference Example 112 to obtain the title compound.

NMR (DMSO-d₆): δ8.60-8.40 (2H, br), 7.99 (2H, d, J=8.3 Hz), 7.72 (2H, d,J=8.3 Hz), 4.33-4.23 (1H, br), 3.22 (3H, s), 2.02-1.72 (2H, m), 0.75(3H, t, J=7.4 Hz)

MS: 214 (M+H)⁺

Reference Example 114 tert-butyl 3-(1-aminopropyl)-4-methoxybenzoate(compound S114)

Instead of the starting material of Reference Example 56, that is, thecompound S55, 3-bromo-4-methoxybenzoic acid was used for the similarprocedure as in Reference Example 56, Reference Example 75, ReferenceExample 76, and Reference Example 164 to obtain the title compound.

NMR (CDCl₃): δ7.88 (1H, d, 1.7 Hz), 7.85 (1H, dd, 8.5, 1.7 Hz), 6.84(1H, d, 8.5 Hz), 4.05 (1H, t, 6.9 Hz), 3.86 (3H, s), 1.82-1.60 (2H, m),1.56 (9H, S), 0.88 (3H, s, 7.4 Hz)

MS: 249 (M−NH₂)⁺

Reference Example 115 tert-butyl 4-[(1R)-1-aminopropyl]-2-nitrobenzoatehydrochloride (compound S101)

A mixed solution of the compound S97 (703 mg),(R)-2,2′-bis(di-4-methylphenylphosphino)-1,1′-binaphthyl ruthenium (II)chloride complex (51 mg), ammonium formate (3.15 g), and 2Mammonia/methanol solution (20 ml) was stirred under a nitrogenatmosphere at 85° C. for 18 hours. Next, ethyl formate (4 ml) was addedto the reaction solution and the mixture was stirred at 85° C. for 18hours. The reaction solution was concentrated, saturated potassiumhydrogensulfate aqueous solution and saturated saline were added, andthe mixture was extracted with ethyl acetate. The organic layer wasdried over with anhydrous sodium sulfate, then concentrated. Ethanol (10ml), distilled water (2.5 ml), and concentrated hydrochloric acid (2.5ml) were added to the residue, the mixture was stirred at 85° C. for 40minutes, then the reaction solution was concentrated to obtain4-[(1R)-1-aminopropyl]-2-nitrobenzoic acid hydrochloride (745 mg). To500 mg of the obtained 4-[(1R)-1-aminopropyl]-2-nitrobenzoic acidhydrochloride, methylene chloride (20 ml) and anhydrous magnesiumsulfate (3.5 g) were added and the mixture was stirred at roomtemperature for 15 minutes. Next, concentrated sulfuric acid (186 μl)was added to the reaction solution, the mixture was stirred at roomtemperature for 5 minutes, then isobutene (3.5 ml) was added and themixture was stirred at room temperature for 24 hours. Saturated sodiumhydrogencarbonate aqueous solution was added to the reaction solutionand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated saline, dried over with anhydrous sodium sulfate,then concentrated. The residue was diluted with ethyl acetate, then 4Nhydrogen chloride/ethyl acetate solution (0.5 ml) was added dropwise inthe obtained solution. The precipitate was collected by filtration toobtain the title compound (358 mg).

NMR (DMSO-d₆): δ8.66 (3H, br), 8.22 (1H, s), 7.96-7.89 (2H, m), 4.38(1H, dd, 8.9, 5.8 Hz), 2.04-1.93 (1H, m), 1.92-1.80 (1H, m), 1.50 (9H,s), 0.77 (3H, t, 7.4 Hz)

MS: 281 (M+H)⁺

Reference Example 116 tert-butyl4-[(1R)-1-isocyanatepropyl]-2-nitrobenzoate (compound S116)

Saturated sodium hydrogencarbonate aqueous solution (15 ml) was added tothe compound S101 (1 g) in methylene chloride (15 ml) solution under icecooling and the mixture was stirred at that temperature for 10 minutes.Next, under ice cooling, trichloromethyl chloroformate (0.38 ml) wasadded to the reaction solution and the mixture was stirred at thattemperature for 20 minutes. The reaction solution was extracted withmethylene chloride. The extract was washed with saturated saline, driedover with anhydrous sodium sulfate, and concentrated to obtain the titlecompound as a crude product (1.02 g).

NMR (CDCl₃): δ7.76 (1H, d, J=1.7 Hz), 7.73 (1H, d, J=7.9 Hz), 7.57 (1H,dd, J=7.9, 1.7 Hz), 4.73 (1H, dd, J=7.5, 5.4 Hz), 1.95-1.80 (2H, m),1.56 (9H, s), 1.01 (3H, t, J=7.3 Hz)

Reference Example 117N-[(2E)-3-(5-chloro-2-methoxyphenyl)-2-({[(4-chlorophenyl)sulfonyl]amino}carbonyl)-2-propenyl]-2,2,2-trifluoroacetoamide(compound S117)

To the compound S6 (620 mg) and 4-chlorobenzenesulfonamide (350 mg) inmethylene chloride (10 ml) solution, 4-dimethylaminopyridine (225 mg)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (460 mg)were added and the mixture was stirred at room temperature for 2 hours.The methylene chloride was distilled off in vacuo, then ethyl acetatewas added. The ethyl acetate solution was successively washed withdistilled water, saturated potassium hydrogensulfate aqueous solution,distilled water, and saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was dried in vacuo to obtain thetitle compound (1.04 g).

Reference Example 118N-(2-chloro-5-{[((2E)-3-(5-chloro-2-methoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoyl)amino]sulfonyl}phenyl)-2,2,2-trifluoroacetoamide(compound S118)

Instead of the starting material compound of Reference Example 117, thatis, 4-chlorobenzenesulfonamide, the compound S57 was used for thesimilar procedure as in Reference Example 117 to obtain the titlecompound.

Reference Example 119 tert-butyl(2E)-2-({[(4-chlorophenyl)sulfonyl]amino}carbonyl)-3-(4-fluorophenyl)-2-propenylcarbamate(compound S119)

Instead of the compound S6 of Reference Example 117, the compound S26was used for the similar procedure as in Reference Example 117 to obtainthe title compound.

NMR (CDCl₃): δ8.07 (2H, d, J=8.6 Hz), 7.8 (1H, s), 7.5 (2H, d, J=8.6Hz), 7.21 (2H, dd, J=8.7, 5.4 Hz), 7.1 (2H, t, J=8.7 Hz), 4.91 (1H, br),4.11 (2H, d, J=6.9 Hz), 1.5 (9H, s)

Reference Example 120N-[(2E)-2-(aminomethyl)-3-(4-fluorophenyl)-2-propenoyl]-4-chlorobenzenesulfonamidehydrochloride (compound S120)

A 1M hydrogen chloride/acetic acid solution (10 ml) was added to thecompound S119 (828 mg) and the mixture was stirred at room temperaturefor 1.5 hours. The reaction solution was diluted with diethylether andthe mixture was stirred under ice cooling for 30 minutes. Theprecipitated solid was collected by filtration to obtain the titlecompound (614 mg).

NMR (CD3OD): δ8.08 (2H, d, J=8.7 Hz), 7.86 (1H, s), 7.63 (2H, d, J=8.7Hz), 7.47 (2H, dd, J=8.7, 5.3 Hz), 7.24 (2H, t, J=8.7 Hz), 3.87 (2H, s)

Reference Example 121allyl(2E)-2-({[(4-chlorophenyl)sulfonyl]amino}carbonyl)-3-(4-methoxymethoxyphenyl)-2-propenylcarbamate(compound S121)

To the compound S32 (1.2 g) and 4-chlorobenzenesulfonamide (710 mg) inmethylene chloride (25 ml) solution, 4-dimethylaminopyridine (460 mg)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (930 mg)were added and the mixture was stirred at room temperature for 1.5hours. The methylene chloride was distilled off in vacuo, then ethylacetate was added. The ethyl acetate solution was successively washedwith distilled water, saturated potassium hydrogensulfate aqueoussolution, distilled water, and saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was dried invacuo to obtain the title compound (1.88 g).

NMR (CDCl₃): δ8.07 (2H, d, J=8.6 Hz), 7.7 (1H, s), 7.5 (2H, d, J=8.6Hz), 7.30-7.21 (2H, m), 7.06 (2H, d, J=8.7 Hz), 5.92 (1H, ddd, J=16.0,10.0, 5.7 Hz), 5.33 (1H, d, J=16.0 Hz), 5.26 (1H, d, J=10.0 Hz),5.25-5.15 (3H, m), 4.65 (2H, d, J=5.7 Hz), 4.2 (2H, d, J=6.7 Hz), 3.47(3H, s)

Reference Example 1222-bromo-N-[(2E)-3-(5-chloro-2-methoxyphenyl)-2-({[(4-chlorophenyl)sulfonyl]amino}carbonyl)-2-propenyl]acetoamide(compound S122)

To the compound S117 (1.01 g) in methanol (9 ml) solution, 2N sodiumhydroxide aqueous solution (2.2 ml) was added and the mixture wasstirred at room temperature for 2 hours. The methanol was distilled offin vacuo, the mixture was diluted with methylene chloride (15 ml), thenbromoacetyl chloride (0.18 ml) was added under ice cooling and themixture was stirred at that temperature for 20 minutes. Next, methylenechloride was distilled off in vacuo and the remaining aqueous mixturewas extracted with ethyl acetate. The organic layer was successivelywashed with saturated sodium hydrogencarbonate aqueous solution,saturated saline, saturated potassium hydrogensulfate aqueous solution,saturated saline, dried over with anhydrous sodium sulfate, andconcentrated to obtain the title compound (930 mg).

Reference Example 123N-[(2E)-2-(aminomethyl)-3-(4-methoxymethoxyphenyl)-2-propenoyl]-4-chlorobenzenesulfonamidehydrochloride (compound S123)

To the compound S121 (500 mg) in tetrahydrofuran (15 ml) suspension,formic acid (0.12 ml), triphenylphosphine (52 mg), andtris(dibenzylideneacetone)dipalladium (46 mg) were added and the mixturewas stirred at room temperature for 2 hours. A 4M hydrogenchloride/dioxane solution was added to the reaction solution, thentetrahydrofuran was distilled off in vacuo. The residue was diluted withmethanol, then the insoluble compound was filtered out and the filtratewas concentrated. The residue was recrystallized frommethanol/diethylether to obtain the title compound (216 mg).

Reference Example 1242-bromo-N-[(2E)-2-({[(4-chlorophenyl)sulfonyl]amino}carbonyl)-3-(4-fluorophenyl)-2-propenyl]acetoamide(compound S124)

To the compound S120 (599 mg) in methylene chloride (10 ml)/distilledwater (3 ml) solution, triethylamine (0.6 ml) and bromoacetyl bromide(0.19 ml) were added under ice cooling and the mixture was stirred atroom temperature for 20 minutes. The reaction solution was diluted withethyl acetate, was successively dried by saturated sodiumhydrogencarbonate aqueous solution, distilled water, saturated potassiumhydrogensulfate aqueous solution, distilled water, and saturated saline,dried over with anhydrous sodium sulfate, then concentrated. The residuewas washed with hexane/ethyl acetate to obtain the title compound as acrude product (522 mg).

NMR (DMSO-d6): δ8.46 (1H, br), 7.97 (2H, d, J=8.6 Hz), 7.71 (2H, d,J=8.6 Hz), 7.60-7.50 (3H, m), 7.27 (2H, t, J=8.8 Hz), 3.99 (2H, d, J=5.0Hz), 3.77 (2H, s)

Example 1(6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 1)

To the compound S122 (915 mg) in N,N-dimethylformamide (50 ml) solution,sodium hydride (60% mineral oil dispersion) (80 mg) was added and themixture was stirred at 60 to 80° C. for 19 hours. Acetic acid (1 ml) wasadded to the reaction solution and the mixture concentrated. Ethylacetate was added to the residue, then the obtained solution wassuccessively washed with saturated sodium hydrogencarbonate aqueoussolution, distilled water, saturated potassium hydrogensulfate aqueoussolution, and saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was recrystallized from ethylacetate to obtain the title compound (373 mg).

NMR (DMSO-d₆): δ8.07-8.02 (1H, br), 7.95 (2H, d, J=8.6 Hz), 7.75 (2H, d,J=8.6 Hz), 7.54 (1H, s), 7.47 (1H, dd, J=8.8, 2.5 Hz), 7.27 (1H, d,J=2.5 Hz), 7.11 (1H, d, J=8.8 Hz), 4.72 (2H, s), 4.18 (2H, d, J=4.2 Hz),3.80 (3H, s), 3.31 (2H, s)

MS: 455 (M+H)⁺

The (3-amino acid derivative and sulfonamide derivative shown in Table Ias starting material compounds were used for the synthesis methods shownin Table I to obtain the title compounds of Examples 2 to 21. Note thatthe β-amino acid derivative and sulfonamide derivative shown in Table Iare compounds shown in the reference examples, commercially availablecompounds, or compounds obtained by derivation from the commerciallyavailable compounds by known methods.

The Synthesis Method A of Table I is a method successively performingoperations similar to Reference Example 117, Reference Example 122, andExample 1, while the Synthesis Method B is a method successivelyperforming operations similar to Reference Example 119, ReferenceExample 120, Reference Example 124, and Example 1.

TABLE I β-amino acid Sulfonamide derivative derivative used as used asEx. starting starting Synthesis No. material material method Ex. 2Compound S26

B Ex. 3 Compound S25

B Ex. 4 Compound S8

A Ex. 5 Compound S9

A Ex. 6 Compound S10

A Ex. 7 Compound S31

B Ex. 8 Compound S6

A Ex. 9 Compound S6

A Ex. 10 Compound S6 Compound S66 A Ex. 11 Compound S6

A Ex. 12 Compound S6 Compound S69 A Ex. 13 Compound S10

A Ex. 14 Compound S10

A Ex. 15 Compound S6

A Ex. 16 Compound S6

A Ex. 17 Compound S6

A Ex. 18 Compound S6

A Ex. 19 Compound S6

A Ex. 20 Compound S12

A Ex. 21 Compound S10

A

Example 2(6E)-6-(4-fluorobenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 2)

NMR (CDCl₃): δ8.03 (2H, d, J=8.6 Hz), 7.62 (1H, s), 7.52 (2H, d, J=8.6Hz), 7.27-7.21 (2H, m), 7.12 (2H, t, J=8.6 Hz), 5.91-5.84 (1H, br), 4.7(2H, s), 4.32 (2H, d, J=4.4 Hz)

MS: 409 (M+H)⁺

Example 3(6E)-4-[(4-chlorophenyl)sulfonyl]-6-(2-naphthylmethylene)-1,4-diazepan-2,5-dione(compound 3)

NMR (CDCl₃): δ8.05 (2H, d, J=8.7 Hz), 7.90-7.81 (4H, m), 7.74 (1H, s),7.58-7.50 (4H, m), 7.35 (1H, dd, J=8.5, 1.4 Hz), 5.92-5.87 (1H, br),4.74 (2H, s), 4.44 (2H, d, J=3.8 Hz)

MS: 441 (M+H)⁺

Example 44-{[(6E)-6-benzylidene-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzonitrile(compound 4)

NMR (DMSO-d₆): δ8.17 (2H, d, J=8.4 Hz), 8.15-8.05 (1H, br), 8.11 (2H, d,J=8.4 Hz), 7.56 (1H, s), 7.51-7.38 (5H, m), 4.75 (2H, s), 4.3 (2H, d,J=4.3 Hz)

MS: 382 (M+H)⁺

Melting point: 239° C. (decomposition)

Example 5(6E)-6-(5-chloro-2-nitrobenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 5)

NMR (CDCl₃): δ8.18 (1H, d, J=8.8 Hz), 8.02 (2H, d, J=8.7 Hz), 7.72 (1H,s), 7.58-7.52 (3H, m), 7.23 (1H, d, J=2 Hz), 5.82 (1H, br), 4.69 (2H,s), 4.05 (1H, d, J=4.4 Hz), 4.04 (1H, d, J=4.3 Hz)

MS: 470 (M+H)⁺

Example 6(6E)-4-[(4-dimethylamino-3-nitrophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 6)

NMR (DMSO-d₆): δ8.28 (1H, d, J=2.4 Hz), 8.04 (1H, br), 7.86 (1H, dd,J=9.3, 2.4 Hz), 7.56 (1H, s), 7.31 (1H, d, J=9.3 Hz), 7.26 (1H, dt,J=8.8, 3 Hz), 7.13-7.07 (2H, m), 4.68 (2H, s), 4.17 (2H, d, J=4.5 Hz),3.79 (3H, s), 2.96 (6H, s)

MS: 493 (M+H)⁺

Example 7(6E)-4-[(4-chlorophenyl)sulfonyl]-6-(3-cyanobenzylidene)-1,4-diazepan-2,5-dione(compound 7)

NMR (DMSO-d₆): δ8.09 (1H, br), 7.96 (2H, d, J=8.7 Hz), 7.90-7.84 (2H,m), 7.77-7.63 (4H, m), 7.50 (1H, s), 4.70 (2H, s), 4.28-4.24 (2H, m)

MS: 416 (M+H)⁺

Example 8(6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(4-chloro-2-methoxyphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 8)

NMR (CDCl₃): δ8.06 (1H, d, J=8.6 Hz), 7.69 (1H, s), 7.32 (1H, dd, J=8.9,2.5 Hz), 7.12 (1H, dd, J=8.6, 1.8 Hz), 7.04 (1H, d, J=2.5 Hz), 6.99 (1H,d, J=1.8 Hz), 6.85 (1H, d, J=8.9 Hz), 5.88 (1H, br), 4.77 (2H, s), 4.18(2H, d, J=4.5 Hz), 3.94 (3H, s), 3.80 (3H, s)

MS: 485 (M+H)⁺

Example 9(6E)-4-[(4-chloro-2-fluorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 9)

NMR (DMSO-d₆): δ8.08 (1H, t, J=4.3 Hz), 8.00 (1H, t, J=8.3 Hz), 7.83(1H, dd, J=10.3, 1.8 Hz), 7.62-7.58 (2H, m), 7.47 (1H, dd, J=9.0, 2.5Hz), 7.27 (1H, d, J=2.5 Hz), 7.12 (1H, d, J=9.0 Hz), 4.70 (2H, s), 4.18(2H, d, J=4.3 Hz), 3.8 (3H, s)

MS: 473 (M+H)⁺

Example 10N-(2-chloro-5-{[(6E)-6-(5-chloro-2-methoxybenzylidene)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}phenyl)-N′-ethylurea(compound 10)

NMR (DMSO-d₆): δ8.90 (1H, d, J=2.2 Hz), 8.31 (1H, s), 8.05 (1H, br),7.68 (1H, d, J=8.4 Hz), 7.53 (1H, s), 7.46 (1H, dd, J=9.0, 2.5 Hz), 7.41(1H, dd, J=8.4, 2.2 Hz), 7.27 (1H, d, J=2.5 Hz), 7.15 (1H, t, J=5.2 Hz),7.11 (1H, d, J=9.0 Hz), 4.68 (2H, s), 4.17 (2H, br), 3.80 (3H, s),3.20-3.11 (2H, m), 1.09 (3H, t, J=7.2 Hz)

MS: 541 (M+H)⁺

Example 11(6E)-4-[(4-chlorobenzyl)sulfonyl]-6-(5-chloro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 11)

NMR (CDCl₃): δ7.76 (1H, s), 7.39-7.32 (5H, m), 7.10 (1H, d, J=2.5 Hz),6.89 (1H, d, J=8.9 Hz), 5.96 (1H, br), 4.83 (2H, s), 4.11 (2H, d, J=4.2Hz), 4.02 (2H, s), 3.86 (3H, s)

MS: 469 (M+H)⁺

Example 12(6E)-6-(5-chloro-2-methoxybenzylidene)-4-{[4-(1H-pyrazol-3-yl)phenyl]sulfonyl}-1,4-diazepan-2,5-dione(compound 12)

NMR (DMSO-d₆): δ13.15 (1H, br), 8.10-8.00 (3H, m), 7.95 (2H, d, J=8.4Hz), 7.85 (1H, br), 7.52 (1H, d, J=2.1 Hz), 7.45 (1H, dd, J=8.9, 2.5Hz), 7.27 (1H, d, J=2.5 Hz), 7.10 (1H, d, J=8.9 Hz), 6.89 (1H, d, J=2.1Hz), 4.73 (2H, s), 4.18 (2H, d, J=3.7 Hz), 3.78 (3H, s)

MS: 487 (M+H)⁺

Example 13(6E)-4-[(6-chloro-3-pyridyl)sulfonyl]-6-(5-fluoro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 13)

NMR (DMSO-d₆): δ8.93 (1H, d, J=2.5 Hz), 8.36 (1H, dd, J=8.5, 2.5 Hz),8.12 (1H, br), 7.86 (1H, d, J=8.5 Hz), 7.59 (1H, s), 7.27 (1H, dt,J=8.7, 3.1 Hz), 7.12-7.07 (2H, m), 4.72 (2H, s), 4.18 (2H, d, J=4.1 Hz),3.79 (3H, s)

MS: 440 (M+H)⁺

Example 14(6E)-4-[(5-chloro-2-thienyl)sulfonyl]-6-(5-fluoro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 14)

NMR (CDCl₃): δ7.77 (1H, s), 7.72 (1H, d, J=4.1 Hz), 7.12-7.06 (1H, m),6.96 (1H, d, J=4.1 Hz), 6.90-6.82 (2H, m), 5.97 (1H, br), 4.61 (2H, s),4.209 (1H, d, J=4.5 Hz), 4.208 (1H, d, J=3.7 Hz), 3.82 (3H, s)

MS: 445 (M+H)⁺

Melting point: 150-153° C.

Example 15(6E)-4-[(5-chloro-4-fluoro-2-methoxyphenyl)sulfonyl]-6-(5-chloro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 15)

NMR (CDCl₃): δ8.21 (1H, d, J=8.1 Hz), 7.72 (1H, s), 7.33 (1H, dd, J=8.8,2.5 Hz), 7.05 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.8 Hz), 6.80 (1H, d,J=10.3 Hz), 5.90 (1H, br), 4.76 (2H, s), 4.19 (2H, d, J=4.4 Hz), 3.93(3H, s), 3.81 (3H, s)

MS: 503 (M+H)⁺

Example 16(6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(2,5-dimethoxyphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 16)

NMR (CDCl₃): δ7.65 (1H, s), 7.64 (1H, d, J=3.0 Hz), 7.32 (1H, dd, J=8.8,2.6 Hz), 7.13 (1H, dd, J=9.0, 3.0 Hz), 7.06 (1H, d, J=2.6 Hz), 6.94 (1H,d, J=9.0 Hz), 6.85 (1H, d, J=8.8 Hz), 5.88 (1H, br), 4.77 (2H, s), 4.177(1H, d, J=3.8 Hz), 4.176 (1H, d, J=4.5 Hz), 3.90 (3H, s), 3.85 (3H, s),3.80 (3H, s)

MS: 481 (M+H)⁺

Example 17(6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(2-methoxy-5-methylphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 17)

NMR (CDCl₃): δ7.94 (1H, d, J=2.0 Hz), 7.66 (1H, s), 7.37 (1H, dd, J=8.5,2.0 Hz), 7.31 (1H, dd, J=8.9, 2.5 Hz), 7.05 (1H, d, J=2.5 Hz), 6.90 (1H,d, J=8.5 Hz), 6.85 (1H, d, J=8.9 Hz), 5.91 (1H, br), 4.78 (2H, s), 4.17(2H, d, J=4.0 Hz), 3.91 (3H, s), 3.79 (3H, s), 2.38 (3H, s)

MS: 465 (M+H)⁺

Example 18(6E)-6-(5-chloro-2-methoxybenzylidene)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]sulfonyl}-1,4-diazepan-2,5-dione(compound 18)

NMR (CDCl₃): δ8.42 (1H, d, J=2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 7.71(1H, s), 7.32 (1H, dd, J=8.8, 2.5 Hz), 7.1 (1H, d, J=8.8 Hz), 7.05 (1H,d, J=2.5 Hz), 6.86 (1H, d, J=8.8 Hz), 5.97 (1H, br), 4.79 (2H, s), 4.20(2H, d, J=4.4 Hz), 4.01 (3H, s), 3.81 (3H, s)

MS: 519 (M+H)⁺

Example 19(6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(2-methoxy-5-nitrophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 19)

NMR (CDCl₃): δ9.04 (1H, d, J=2.8 Hz), 8.47 (1H, dd, J=9.1, 2.8 Hz), 7.75(1H, s), 7.33 (1H, dd, J=8.8, 2.5 Hz), 7.12 (1H, d, J=9.1 Hz), 7.04 (1H,d, J=2.5 Hz), 6.86 (1H, d, J=8.8 Hz), 5.80 (1H, br), 4.80 (2H, s), 4.22(2H, d, J=4.4 Hz), 4.08 (3H, s), 3.81 (3H, s)

MS: 496 (M+H)⁺

Example 20(6E)-6-(3-chloro-5-fluoro-2-methoxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 20)

NMR (CDCl₃): δ8.03 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.53 (2H, d, J=8.8Hz), 7.19 (1H, dd, J=7.7, 3.0 Hz), 7.78 (1H, dd, J=8.3, 3.0 Hz), 5.8(1H, br), 4.72 (2H, s), 4.153 (1H, d, J=3.6 Hz), 1.151 (1H, d, J=4.7Hz), 3.72 (3H, s)

MS: 473 (M+H)⁺

Example 21 methyl3-{[(6E)-6-(5-fluoro-2-methoxybenzylidene)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}propanoatetartrate(compound 21)

NMR (CDCl₃): δ7.83 (1H, s), 7.10 (1H, dt, J=8.9, 3.0 Hz), 6.92-6.86 (2H,m), 5.92 (1H, br), 4.56 (2H, s), 4.252 (1H, d, J=3.7 Hz), 4.251 (1H, d,J=4.6 Hz), 3.98 (2H, t, J=7.4 Hz), 3.85 (3H, s), 3.73 (3H, s), 2.88 (2H,t, J=7.4 Hz)

MS: 415 (M+H)⁺

Example 22(6E)-4-[(3-amino-4-chlorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 22)

To the compound S118 (2.25 g), methanol (20 ml) and a 2M sodiumhydroxide aqueous solution (5.8 ml) were added, the mixture was stirredat room temperature for 23 hours, then the mixture was further stirredat 60° C. for 7 hours. The methanol was distilled off in vacuo,methylene chloride (20 ml) was added to the remaining aqueous solution,bromoacetyl bromide (0.35 ml) was further added under ice cooling, thenthe mixture was stirred at that temperature for 20 minutes. Themethylene chloride was distilled off in vacuo, ethyl acetate andsaturated sodium hydrogencarbonate aqueous solution were added to theremaining solution, and the aqueous layer and the organic layer wereseparated. The organic layer was washed with saturated saline, driedover with anhydrous sodium sulfate, and diluted withN,N-dimethylformamide (100 ml). The ethyl acetate was distilled off invacuo. The remaining N,N-dimethylformamide solution was stirred at 60°C. for 14 hours. The reaction solution was concentrated, then theresidue was diluted with ethyl acetate. The obtained solution wassuccessively washed with distilled water and saturated saline, driedover with anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (chloroform/acetone=4/1) toobtain the title compound (520 mg).

NMR (DMSO-d₆): δ8.04 (1H, t, J=4.4 Hz), 7.54 (1H, s), 7.46 (1H, dd,J=9.0, 2.5 Hz), 7.47-7.41 (2H, m), 7.27 (1H, d, J=2.5 Hz), 7.11 (1H, d,J=9.0 Hz), 6.98 (1H, dd, J=8.3, 2.2 Hz), 5.96 (2H, s), 4.66 (2H, s),4.16 (2H, d, J=4.4 Hz), 3.8 (3H, s)

MS: 470 (M+H)⁺

Reference Example 125 tert-butyl(2E)-2-({[(4-chloroanilino)carbonyl]amino}carbonyl)-3-(5-chloro-2-methoxyphenyl)-2-propenylcarbamate(compound S125)

To N-(4-chlorophenyl)urea (1.9 g) in N,N-dimethylformamide (35 ml)solution, sodium hydride (60% mineral oil dispersion) (460 mg) was addedand the mixture was stirred at room temperature for 1 hour. Next, to thereaction mixture, a mixed solution obtained by adding1,1′-carbonyldiimidazole (1.9 g) to the compound S23 (4 g) intetrahydrofuran (35 ml) solution under ice cooling and stirring themixture at room temperature for 45 minutes was added and the reactionmixture was stirred at room temperature for 16 hours. The reactionmixture was diluted with ethyl acetate and saturated potassiumhydrogensulfate aqueous solution, and the obtained solution wasseparated. The organic layer was washed with saturated saline, driedover with anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=1/1)to obtain the title compound (2.6 g).

NMR (CDCl₃): δ10.79 (1H, br), 9.46 (1H, br), 7.7 (1H, s), 7.5 (2H, d,J=8.8 Hz), 7.33 (1H, dd, J=8.8, 2.5 Hz), 7.30-7.20 (3H, m), 6.87 (1H, d,J=8.8 Hz), 4.92 (1H, br), 4.15 (2H, d, J=6.4 Hz), 3.84 (3H, s), 1.46(9H, s)

Reference Example 1262-bromo-N-[(2E)-2-({[(4-chloroanilino)carbonyl]amino}carbonyl)-3-(5-chloro-2-methoxyphenyl)-2-propenyl]acetoamide(compound S126)

A mixed solution of the compound S125 (2.6 g) and a 1M hydrochloricacid/acetic acid solution (15 ml) was stirred at room temperature for 1hour. The reaction solvent was distilled off in vacuo. The residue wasdiluted with methylene chloride (50 ml) and distilled water (10 ml),bromoacetyl chloride (0.5 ml) and triethylamine (1.7 ml) were added tothe obtained solution under ice cooling, and the mixture was stirred atthat temperature for 20 minutes. The reaction solution was diluted withN,N-dimethylformamide and ethyl acetate, was successively washed withdistilled water, saturated sodium hydrogencarbonate aqueous solution,distilled water, saturated potassium hydrogensulfate aqueous solution,and saturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was washed with ethyl acetate to obtain thetitle compound (2.5 g).

NMR (DMSO-d₆): δ10.8 (1H, s), 10.69 (1H, s), 8.55 (1H, br), 7.65-7.55(3H, m), 7.51 (1H, s), 7.45 (1H, dd, J=9.0, 2.2 Hz), 7.4 (2H, d, J=8.8Hz), 7.12 (1H, d, J=9.0 Hz), 4.09 (2H, d, J=5.0 Hz), 3.86 (2H, s), 3.82(3H, s)

Example 23(6E)-6-(5-chloro-2-methoxybenzylidene)-N-(4-chlorophenyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 23)

To the compound S126 (2.08 g) in N,N-dimethylformamide (150 ml)solution, sodium hydride (60% mineral oil dispersion) (150 mg) wasadded. The mixture was stirred at room temperature for 30 minutes, thenwarmed to 60° C. and stirred for 1 hour. Next, acetic acid (0.5 ml) wasadded to the reaction solution and the mixture concentrated. The residuewas diluted with ethyl acetate. The obtained solution was successivelywashed with saturated sodium hydrogencarbonate aqueous solution,distilled water, saturated potassium hydrogensulfate aqueous solution,and saturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was recrystallized from hexane/ethyl acetateto obtain the title compound (1.26 g).

NMR (CDCl₃): δ11.23 (1H, s), 7.52 (2H, d, J=8.8 Hz), 7.48 (1H, s), 7.35(1H, dd, J=8.8, 2.5 Hz), 7.29 (2H, d, J=8.8 Hz), 7.14 (1H, d, J=2.5 Hz),6.89 (1H, d, J=8.8 Hz), 5.90-5.84 (1H, br), 4.74 (2H, s), 4.30 (2H, dd,J=3.3, 1.9 Hz), 3.87 (3H, s)

MS: 434 (M+H)⁺

Example 24(6E)-6-(5-chloro-2-methoxybenzylidene)-3,7-dioxo-N-[(1R)-1-phenylethyl]-1,4-diazepan-1-carboxamide(compound 24) (enantiomer of Compound 25)

Instead of the starting material compound of Reference Example 125, thatis, N-(4-chlorophenyl)urea, the compound S72 was used to successivelyperform the similar procedures as with Reference Example 125, ReferenceExample 126, and Example 23 to obtain the title compound.

NMR (CDCl₃): δ9.41 (1H, d, J=7.4 Hz), 7.40 (1H, s), 7.37-7.21 (6H, m),7.11 (1H, d, J=2.4 Hz), 6.87 (1H, d, J=8.8 Hz), 6.53-6.47 (1H, br),5.12-5.03 (1H, m), 4.71 (1H, d, J=16.5 Hz), 4.57 (1H, d, J=16.5 Hz),4.23 (2H, t, J=1.4 Hz), 3.84 (3H, s), 1.58 (3H, d, J=6.9 Hz)

MS: 428 (M+H)⁺

Example 25(6E)-6-(5-chloro-2-methoxybenzylidene)-3,7-dioxo-N-[(1S)-1-phenylethyl]-1,4-diazepan-1-carboxamide(compound 25) (enantiomer of Compound 24)

Instead of the starting material compound of Reference Example 125, thatis, N-(4-chlorophenyl)urea, N-[(1S)-1-phenylethyl]urea was used tosuccessively perform the similar procedures as with Reference Example125, Reference Example 126, and Example 23 to obtain the title compound.

MS: 428 (M+H)⁺

Example 26(6E)-6-(5-chloro-2-methoxybenzylidene)-N-(5-chloro-2-pyridyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 26)

Instead of the starting material compound of Reference Example 125, thatis, N-(4-chlorophenyl)urea, N-(2-pyridyl)urea was used to successivelyperform the similar procedures as with Reference Example 125, ReferenceExample 126, and Example 23 to obtain the title compound.

NMR (DMSO-d₆): δ11.68 (1H, s), 8.40 (1H, d, J=2.5 Hz), 8.03 (1H, d,J=9.0 Hz), 7.98 (1H, dd, J=9.0, 2.5 Hz), 7.93-7.89 (1H, br), 7.51 (1H,s), 7.47 (1H, dd, J=8.8, 2.6 Hz), 7.39 (1H, d, J=2.6 Hz), 7.14 (1H, d,J=8.8 Hz), 4.59 (2H, s), 4.21 (2H, s), 3.84 (3H, s)

MS: 435 (M+H)⁺

Reference Example 127 tert-butyl(2E)-3-(5-chloro-2-methoxyphenyl)-2-{[(trifluoroacetyl)amino]methyl}-2-propenoate(compound S127)

To the compound S6 (2.81 g) in methylene chloride (15 ml)/tert-butylalcohol (15 ml) solution, N,N′-diisopropyl-O-tert-butylisourea (7 ml)was added and the mixture was stirred at room temperature for 17 hours.The reaction solution was concentrated, the precipitate was removed byfiltration, then the filtrate was concentrated. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate, ethylacetate: 10 to 20%) to obtain the title compound (1.79 g).

Reference Example 128 tert-butyl(2E)-3-(5-chloro-2-methoxyphenyl)-2-{[methyl(trifluoroacetyl)amino]methyl}-2-propenoate(compound S128)

To the compound S127 (1.79 g) in tetrahydrofuran (50 ml) solution,sodium hydride (60% mineral oil dispersion) (0.2 g) was added under icecooling and the mixture was stirred at that temperature for 10 minutes.Next, methyl iodide (0.42 ml) was added to the reaction solution underice cooling, and the mixture was stirred at room temperature for 14hours. Distilled water was added to the reaction solution and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated saline, dried over with anhydrous magnesium sulfate, thenconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate, ethyl acetate: 10 to 50%) toobtain the title compound (1.62 g).

Reference Example 129 tert-butyl(2E)-3-(5-chloro-2-methoxyphenyl)-2-[(methylamino)methyl]-2-propenoate(compound S129)

To the compound S128 (1.62 g) in ethanol (50 ml) solution, 1N sodiumhydroxide aqueous solution was added and the mixture was stirred at roomtemperature for 3 hours. The reaction solution was concentrated,distilled water was added to the residue, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,dried over with anhydrous magnesium sulfate, then concentrated to obtainthe title compound (1.21 g).

Reference Example 130 tert-butyl(2E)-2-{[{[(tert-butoxycarbonyl)amino]acetyl}(methyl)amino]methyl}-3-(5-chloro-2-methoxyphenyl)-2-propenoate(compound S130)

To the compound S129 (1.21 g) in methylene chloride (50 ml) solution,N-tert-butoxycarbonyl glycine (0.68 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.89 g)were added and the mixture was stirred at room temperature for 15 hours.The reaction solution was concentrated, distilled water was added to theresidue, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline, dried over with anhydrousmagnesium sulfate, then concentrated. The residue was purified by silicagel column chromatography (hexane/ethyl acetate, ethyl acetate: 20 to50%) to obtain the title compound (1.58 g).

Reference Example 131(2E)-2-{[(aminoacetyl)(methyl)amino]methyl}-3-(5-chloro-2-methoxyphenyl)-2-propenoicacid (compound S131)

A mixed solution of the compound S130 (1.58 g) and a 4N hydrogenchloride/1,4-dioxane solution (50 ml) was stirred at room temperaturefor 22 hours. The reaction solution was concentrated, diethylether wasadded to the precipitated solid, and the insoluble compound wascollected by filtration to obtain the title compound (1.09 g).

Reference Example 132(6E)-6-(5-chloro-2-methoxybenzylidene)-1-methyl-1,4-diazepan-2,5-dione(compound S132)

To the compound S131 (1.09 g) in methylene chloride (312 ml) solution,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g) and1-hydroxybenzotriazole (0.84 g) were added and the mixture was stirredat room temperature for 19 hours. The reaction solution wasconcentrated, distilled water was added to the residue, and the mixturewas extracted with ethyl acetate. The organic layer was successivelywashed with saturated potassium hydrogensulfate aqueous solution,saturated saline, saturated sodium hydrogencarbonate aqueous solution,and saturated saline, dried over with anhydrous magnesium sulfate, thenconcentrated. Diethylether was added to the precipitated solid, and theinsoluble compound was collected by filtration to obtain the titlecompound (0.61 g).

NMR (DMSO-d₆): δ8.19 (1H, br), 7.62 (1H, s), 7.42 (1H, dd, J=8.9, 2.5Hz), 7.22 (1H, d, J=2.5 Hz), 7.11 (1H, d, J=8.9 Hz), 4.32 (2H, s), 3.88(2H, d, J=5.5 Hz), 3.81 (3H, s). 2.69 (3H, s)

Reference Example 1334-nitrophenyl(6E)-6-(5-chloro-2-methoxybenzylidene)-4-methyl-3,7-dioxo-1,4-diazepan-1-carboxylate(compound S133)

To the compound S132 (503 mg) in tetrahydrofuran (40 ml) solution,p-nitrophenyl chlorocarbonate (2.58 g) and triethylamine (1.78 ml) wereadded in stages until the compound of Reference Example 132 disappeared.The mixture was stirred at room temperature for a total of 23 hours. Thereaction solution was concentrated, distilled water was added to theresidue, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline, dried over with anhydrousmagnesium sulfate, then concentrated. The residue was purified by silicagel column chromatography (hexane/ethyl acetate, ethyl acetate: 50 to100%) to obtain the title compound (225 mg).

Example 27(6E)-6-(5-chloro-2-methoxybenzylidene)-4-methyl-3,7-dioxo-N-[(1R)-1-phenylethyl]-1,4-diazepan-1-carboxamide(compound 27)

To the compound S133 (103 mg) in 1,4-dioxane (5 ml) suspension,(R)-(+)-1-phenylethylamine (29 μl) was added and the mixture was stirredat room temperature for 2.5 hours. The reaction solution wasconcentrated, then the residue was purified by silica gel columnchromatography (hexane/ethyl acetate, ethyl acetate: 50% to 100%) toobtain the title compound (101 mg).

NMR (DMSO-d₆): δ9.37 (1H, d, J=7.3 Hz), 7.45 (1H, dd, J=8.9, 2.6 Hz),7.39-7.31 (6H, m), 7.29-7.22 (1H, m), 7.12 (1H, d, J=8.9 Hz), 4.95-4.86(1H, m), 4.58 (1H, d, J=15.4 Hz), 4.53 (1H, d, J=15.4 Hz), 4.38 (1H, d,J=16.8 Hz), 4.33 (1H, d, J=16.8 Hz), 3.81 (3H, s), 2.78 (3H, s), 1.44(3H, d, J=6.9 Hz)

MS: 442 (M+H)⁺

Example 28(6E)-N-benzyl-6-(5-chloro-2-methoxybenzylidene)-N,4-dimethyl-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 28)

Instead of the starting material compound of Example 27, that is,(R)-(+)-1-phenylethylamine, N-methylbenzylamine was used for the similarprocedure as with Example 27 to obtain the title compound.

NMR (DMSO-d₆): δ7.65 (1H, br), 7.45 (1H, dd, J=8.8, 2.5 Hz), 7.40-7.31(4H, m), 7.30-7.25 (2H, m), 7.13 (1H, d, J=8.8 Hz), 4.58 (2H, br), 4.38(2H, br), 4.30 (2H, br), 3.82 (3H, s), 2.78 (6H, s)

MS: 422 (M+H)⁺

Example 296-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 29)

To the compound 1 (1.26 g) in tetrahydrofuran (400 ml) solution, 5%platinum carbon (sulfided catalyst) (400 mg) was added and the mixturewas stirred under hydrogen atmosphere at room temperature for 15 hours.Next, the catalyst was filtered out and the filtrate was concentrated.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=3/2 to 2/1), then the obtained purified productwas recrystallized from hexane/ethyl acetate to obtain the titlecompound (915 mg).

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.19 (1H,dd, J=8.8, 2.6 Hz), 7.01 (1H, d, J=2.6 Hz), 6.77 (1H, d, J=8.8 Hz), 5.71(1H, br), 5.00 (1H, d, J=17.7 Hz), 4.39 (1H, d, J=17.7 Hz), 3.79 (3H,s), 3.50-3.40 (1H, m), 3.26-3.09 (3H, m), 2.52 (1H, dd, J=14.1, 9.1 Hz)

MS: 457 (M+H)⁺

Melting point: 110-112° C.

As the starting material compounds, the benzylidene derivatives orβ-amino acid derivatives and sulfonamide derivatives shown in Table IIto Table VI were used by the synthesis methods shown in Table II toTable VI to obtain the compounds of Example 30 to Example 89. Note thatthe β-amino acid derivatives, sulfonamide derivatives, and benzylidenederivatives shown in Table II to Table VI are compounds shown in thereference examples or examples and commercially available compounds orcompounds obtained by derivation from commercially available compoundsby known methods.

The Synthesis Method C shown in Table II to Table VI is a method thesimilar as that of Example 29, the Synthesis Method D is a methodsuccessively performing the similar procedures as Reference Example 119,Reference Example 120, Reference Example 124, Example 1, and Example 29,and the Synthesis Method E is a method successively performing thesimilar procedures as in Reference Example 117, Reference Example 122,Example 1, and Example 29.

TABLE II β-amino Benzylidene acid derivative derivative Sulfonamide Ex.used as used as derivative used Synthesis no. material material asmaterial method Ex. 30 — Compound S7

D Ex. 31 — Compound S28

D Ex. 32 — Compound S27

D Ex. Compound — — C 33 2 Ex. 34 — Compound S24

D Ex. Compound — — C 35 3 Ex. Compound — — C 36 4 Ex. 37 — Compound S29

D Ex. 38 — Compound S30

D Ex. 39 — Compound S13

E Ex. 40 — Compound S53

D Ex. 41 — Compound S10

E

TABLE III β-amino amino Benzylidene acid derivative derivative used asused as Sulfonamide derivative used Ex. no. material material asmaterial Synthesis method Ex. 42 — Compound S6

E Ex. 43 — Compound S23

D Ex. 44 — Compound S38

D Ex. 45 — Compound S38

D Ex. 46 — Compound S10 Compound S60 E Ex. 47 — Compound S21

E Ex. 48 Compound 8 — — C Ex. 49 Compound 9 — — C Ex. 50 — Compound S6Compound S67 E Ex. 51 — Compound S6 Compound S61 E Ex. 52 — Compound S6Compound S59 E Ex. 53 Compound 7 — — C

TABLE IV Benzylidene derivative β-amino used as acid derivativeSulfonamide derivative used Ex. no. material used as material asmaterial Synthesis method Ex. 54 — Compound S14

E Ex. 55 Compound 10 — — C Ex. 56 Compound 11 — — C Ex. 57 Compound 195— — C Ex. 58 Compound 12 — — C Ex. 59 — Compound S11

E Ex. 60 Compound 183 — — C Ex .61 Compound 182 — — C Ex. 62 — CompoundS6 Compound S65 E Ex. 63 Compound 182 — — C Ex. 64 Compound 184 — — CEx. 65 Compound 13 — — C

TABLE V β-amino Syn- Benzylidene acid the- derivative derivativeSulfonamide sis Ex. used as used as derivative used meth- no. materialmaterial as material od Ex. Compound 14 — — C 66 Ex. 67 — Compound S15

E Ex. Compound 15 — — C 68 Ex. Compound 16 — — C 69 Ex. Compound 17 — —C 70 Ex. Compound 18 — — C 71 Ex. 72 — Compound S10

E Ex. 73 — Compound S10

E Ex. 74 — Compound S10

E Ex. 75 — Compound S10

E Ex. 76 — Compound S10

E Ex. 77 — Compound S10

E

TABLE VI β-amino Benzylidene acid derivative derivative Sulfonamide Ex.used as used as derivative used Synthesis no. material material asmaterial method Ex. Compound 21 — — C 78 Ex. 79 — Compound S19

E Ex. 80 — Compound S20

E Ex. 81 — Compound S16

E Ex. 82 — Compound S17

E Ex. 83 — Compound S18

E Ex. Compound 23 — — C 84 Ex. Compound 24 — — C 85 Ex. Compound 25 — —C 86 Ex. Compound 26 — — C 87 Ex. Compound 27 — — C 88 Ex. Compound 28 —— C 89

Example 30 6-benzyl-4-(phenylsulfonyl)-1,4-diazepan-2,5-dione (compound30)

NMR (CDCl₃): δ8.03 (2H, d, J=7.6 Hz), 7.66 (1H, t, J=7.6 Hz), 7.55 (2H,t, J=7.6 Hz), 7.32-7.20 (3H, m), 7.11 (2H, d, J=6.9 Hz), 5.73 (1H, br),5.02 (1H, d, J=17.7 Hz), 4.42 (1H, d, J=17.7 Hz), 3.38-3.12 (4H, m),2.53 (1H, dd, J=14.3, 9.0 Hz)

MS: 359 (M+H)⁺

Example 316-(3-chlorobenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 31)

NMR (CDCl₃): δ7.96 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz), 7.24-7.22(2H, m), 7.11 (1H, s), 7.05-6.98 (1H, m), 5.67 (1H, br), 5.00 (1H, d,J=17.7 Hz), 4.42 (1H, d, J=17.7 Hz), 3.39-3.25 (2H, m), 3.23-3.14 (2H,m), 2.53 (1H, dd, J=14.4, 8.4 Hz)

MS: 427 (M+H)⁺

Example 326-(4-chlorobenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 32)

NMR (CDCl₃): δ7.95 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 7.30-7.24(2H, m), 7.06 (2H, d, J=8.3 Hz), 5.68 (1H, br), 4.98 (1H, d, J=17.7 Hz),4.41 (1H, d, J=17.7 Hz), 3.36-3.24 (2H, m), 3.22-3.13 (2H, m), 2.54 (1H,dd, J=14.3, 8.0 Hz)

MS: 427 (M+H)⁺

Example 336-(4-fluorobenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 33)

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.09 (2H,dd, J=8.5, 5.4 Hz), 6.98 (2H, t, J=8.5 Hz), 5.69 (1H, br), 4.98 (1H, d,J=17.7 Hz), 4.42 (1H, d, J=17.7 Hz), 3.35-3.25 (2H, m), 3.21-3.12 (2H,m), 2.54 (1H, dd, J=14.3, 8.0 Hz)

MS: 411 (M+H)⁺

Example 346-(4-cyanobenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 34)

NMR (DMSO-d₆): δ7.92 (2H, d, J=8.8 Hz), 7.86 (1H, br), 7.74 (2H, d,J=8.1 Hz), 7.72 (2H, d, J=8.8 Hz), 7.43 (2H, d, J=8.1 Hz), 4.90 (1H, d,J=17.6 Hz), 4.54 (1H, d, J=17.6 Hz), 3.89-3.79 (1H, m), 3.07-2.94 (3H,m), 2.61 (1H, dd, J=14.5, 8.3 Hz)

MS: 418 (M+H)⁺

Example 354-[(4-chlorophenyl)sulfonyl]-6-(2-naphthylmethyl)-1,4-diazepan-2,5-dione(compound 35)

NMR (CDCl₃): δ7.97 (2H, d, J=8.6 Hz), 7.82-7.73 (3H, m), 7.56 (1H, s),7.54-7.42 (4H, m), 7.23 (1H, dd, J=8.4, 1.5 Hz), 5.76 (1H, br), 4.97(1H, d, J=17.6 Hz), 4.43 (1H, d, J=17.6 Hz), 3.49-3.18 (4H, m), 2.72(1H, dd, J=14.0, 8.6 Hz)

MS: 443 (M+H)⁺

Example 364-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzonitrile (compound36)

NMR (CDCl₃): δ8.14 (2H, d, J=8.5 Hz), 7.84 (2H, d, J=8.5 Hz). 7.34-7.22(3H, m), 7.11 (2H, d, J=6.9 Hz), 5.67 (1H, br), 4.96 (1H, d, J=17.6 Hz),4.46 (1H, d, J=17.6 Hz), 3.39-3.28 (2H, m), 3.25-3.15 (2H, m), 2.57 (1H,dd, J=14.3, 8.7 Hz)

MS: 384 (M+H)⁺

Example 374-[(4-chlorophenyl)sulfonyl]-6-(3-methylbenzyl)-1,4-diazepan-2,5-dione(compound 37)

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 7.25 (1H,s), 7.18 (1H, t, J=7.5 Hz), 7.05 (1H, d, J=7.5 Hz), 6.95-6.86 (2H, m),6.03-5.98 (1H, br), 4.95 (1H, d, J=17.6 Hz), 4.42 (1H, d, J=17.6 Hz),3.34-3.23 (2H, m), 3.20-3.10 (2H, m), 2.50 (1H, dd, J=14.5, 9.1 Hz),2.31 (3H, s)

MS: 407 (M+H)⁺

Melting point: 64-66° C.

Example 384-[(4-chlorophenyl)sulfonyl]-6-[3-(trifluoromethyl)benzyl]-1,4-diazepan-2,5-dione(compound 38)

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (3H, d, J=8.7 Hz), 7.42 (1H,t, J=7.8 Hz), 7.39 (1H, s), 7.33 (1H, d, J=7.8 Hz), 5.68-5.62 (1H, br),5.02 (1H, d, J=17.6 Hz), 4.42 (1H, d, J=17.6 Hz), 3.40-3.16 (4H, m),2.63 (1H, dd, J=14.3, 7.8 Hz)

MS: 461 (M+H)⁺

Example 396-(5-chloro-2-ethoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 39)

NMR (CDCl₃): δ7.96 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz), 7.16 (1H,dd, J=8.8, 2.4 Hz), 7.02 (1H, d, J=2.4 Hz), 6.75 (1H, d, J=8.8 Hz), 5.68(1H, br), 5.01 (1H, d, J=17.8 Hz), 4.36 (1H, d, J=17.8 Hz), 4.01 (2H, q,J=7.0 Hz), 3.52-3.42 (1H, m), 3.28-3.06 (3H, m), 2.56 (1H, dd, J=14.1,9.0 Hz), 1.37 (3H, t, J=7.0 Hz)

MS: 471 (M+H)⁺

Example 406-(5-chloro-2-butoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 40)

NMR (CDCl₃): δ7.96 (2H, d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz), 7.17 (1H,dd, J=8.7, 2.5 Hz), 7.02 (1H, d, J=2.5 Hz), 6.76 (1H, d, J=8.7 Hz),5.66-5.61 (1H, br), 5.02 (1H, d, J=17.6 Hz), 4.36 (1H, d, J=17.6 Hz),3.94 (2H, t, J=6.5 Hz), 3.51-3.43 (1H, m), 3.29-3.07 (3H, m), 2.53 (1H,dd, J=14.0, 9.0 Hz), 1.77-1.68 (2H, m), 1.47-1.38 (2H, m), 0.95 (3H, t,J=7.4 Hz)

MS: 499 (M+H)⁺

Example 414-[(4-chlorophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 41)

NMR (CDCl₃): δ7.96 (2H, d, J=7.0 Hz), 7.52 (2H, d, J=7.0 Hz), 6.97-6.90(1H, m), 6.82-6.76 (2H, m), 5.70-5.65 (1H, br), 5.00 (1H, d, J=17.6 Hz),4.40 (1H, d, J=17.6 Hz), 3.79 (3H, s), 3.52-3.40 (1H, m), 3.29-3.21 (1H,m), 3.19-3.09 (2H, m), 2.55 (1H, dd, J=14.0, 8.8 Hz)

MS: 439 (M+H)⁺

Example 426-(5-chloro-2-methoxybenzyl)-4-[(4-chloro-2-methylphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 42)

NMR (CDCl₃): δ8.10 (1H, d, J=8.6 Hz), 7.37 (1H, dd, J=8.6, 2 Hz), 7.29(1H, d, J=2.0 Hz), 7.19 (1H, dd, J=8.8, 2.6 Hz), 6.97 (1H, d, J=2.6 Hz),6.78 (1H, d, J=8.8 Hz), 5.82 (1H, br), 5.11 (1H, d, J=17.9 Hz), 4.42(1H, d, J=17.9 Hz), 3.80 (3H, s), 3.49-3.40 (1H, m), 3.29-3.14 (2H, m),3.09 (1H, dd, J=14.2, 4.6 Hz), 2.52 (3H, s), 2.49 (1H, dd, J=14.2, 9.3Hz)

MS: 471 (M+H)⁺

Example 43 methyl2,4-dichloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoate(compound 43)

NMR (CDCl₃): δ8.79 (1H, s), 7.60 (1H, s), 7.18 (1H, dd, J=8.9, 2.6 Hz),6.97 (1H, d, J=2.6 Hz), 6.78 (1H, d, J=8.9 Hz), 5.99 (1H, br), 5.12 (1H,d, J=18.0 Hz), 4.46 (1H, d, J=18.0 Hz), 3.98 (3H, s), 3.81 (3H, s),3.52-3.42 (1H, m), 3.30-3.26 (2H, m), 3.06 (1H, dd, J=14.2, 4.9 Hz),2.51 (1H, dd, J=14.2, 9.0 Hz)

MS: 548 (M+H)⁺

Example 44rel-(6R,7R)-6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-7-methyl-1,4-diazepan-2,5-dione(compound 44)

NMR (CDCl₃): δ7.93 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz), 7.17 (1H,dd, J=8.7, 2.5 Hz), 7.11 (1H, d, J=2.5 Hz), 6.75 (1H, d, J=8.7 Hz), 5.40(1H, br), 4.74 (1H, d, J=16.9 Hz), 4.47 (1H, d, J=19.6 Hz), 3.80 (3H,s), 3.39-3.29 (1H, m), 3.14-3.01 (2H, m), 2.79 (1H, d, J=10.1 Hz), 1.33(3H, d, J=6.3 Hz)

MS: 471 (M+H)⁺

Example 45rel-(6R,7S)-6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-7-methyl-1,4-diazepan-2,5-dione(compound 45)

NMR (CDCl₃): δ7.97 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.18 (1H,dd, J=8.7, 2.6 Hz), 7.00 (1H, d, J=2.6 Hz), 6.67 (1H, d, J=8.7 Hz), 5.97(1H, brd, J=4.0 Hz), 5.07 (1H, d, J=18.0 Hz), 4.31 (1H, d, J=18.0 Hz),3.78 (3H, s), 3.60-3.56 (1H, m), 3.42-3.33 (1H, m), 3.03 (1H, dd,J=14.2, 5.4 Hz), 2.57 (1H, dd, J=14.2, 8.8 Hz), 0.97 (3H, d, J=6.6 Hz)

MS: 471 (M+H)⁺

Example 464-[(3-amino-4-chlorophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dionehydrochloride (compound 46)

NMR (DMSO-d₆): δ7.83 (1H, br), 7.43 (1H, d, J=8.3 Hz), 7.39 (1H, d,J=2.2 Hz), 7.12-6.91 (4H, m), 4.85 (1H, d, J=17.5 Hz), 4.47 (1H, d,J=17.5 Hz), 3.88-3.42 (1H, m), 3.74 (3H, s), 3.02-2.97 (2H, m), 2.85(1H, dd, J=14.3, 4.7 Hz), 2.58-2.48 (1H, m)

MS: 456 (M+H)⁺

Example 476-(5-chloro-2-ethoxymethoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 47)

NMR (CDCl₃): δ7.97 (2H, d, J=8.7 Hz), 7.53 (2H, d, J=8.7 Hz), 7.17 (1H,dd, J=8.4, 2.6 Hz), 7.04 (1H, d, J=8.4 Hz), 7.03 (1H, d, J=2.6 Hz),5.81-5.73 (1H, br), 5.21 (2H, dd, J=11.3, 6.9 Hz), 5.01 (1H, d, J=17.6Hz), 4.38 (1H, d, J=17.6 Hz), 3.66 (2H, dd, J=14.1, 6.9 Hz), 3.51-3.42(1H, m), 3.32-3.12 (3H, m), 2.55 (1H, dd, J=14.2, 9.2 Hz), 1.21 (3H, t,J=7.0 Hz)

MS: 523 (M+Na)⁺

Example 486-(5-chloro-2-methoxybenzyl)-4-[(4-chloro-2-methoxyphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 48)

NMR (CDCl₃): δ8.04 (1H, d, J=8.5 Hz), 7.19 (1H, dd, J=8.8, 2.6 Hz), 7.13(1H, dd, J=8.5, 2.6 Hz), 7.00-6.97 (2H, m), 6.78 (1H, d, J=8.8 Hz), 5.79(1H, br), 5.14 (1H, d, J=18.1 Hz), 4.40 (1H, d, J=18.1 Hz), 3.87 (3H,s), 3.81 (3H, s), 3.50-3.40 (1H, m), 3.25-3.14 (2H, m), 3.10 (1H, dd,J=14.2, 4.4 Hz), 2.49 (1H, dd, J=14.2, 9.3 Hz)

MS: 487 (M+H)⁺

Example 494-[(4-chloro-2-fluorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 49)

NMR (CDCl₃): δ8.05 (1H, t, J=8.2 Hz), 7.35 (1H, d, J=8.2 Hz), 7.24-7.17(2H, m), 6.99 (1H, d, J=2.5 Hz), 6.78 (1H, d, J=8.5 Hz), 5.91 (1H, br),5.09 (1H, d, J=18.0 Hz), 4.41 (1H, d, J=18.0 Hz), 3.81 (3H, s),3.51-3.42 (1H, m), 3.34-3.21 (2H, m), 3.08 (1H, dd, J=14.2, 4.8 Hz),2.51 (1H, dd, J=14.2, 9.1 Hz)

MS: 475 (M+H)⁺

Example 50 tert-butyl2-amino-4-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoate(compound 50)

NMR (DMSO-d₆): δ7.84 (1H, br), 7.81 (1H, d, 8.5 Hz), 7.41 (1H, d, 1.4Hz), 7.26-7.23 (2H, m), 7.03 (2H, s), 6.97 (1H, d, 8.4 Hz), 6.86 (1H,dd, 8.5, 1.4 Hz), 4.88 (1H, d, 17.5 Hz), 4.48 (1H, d, 17.5 Hz), 3.75(3H, s), 3.73-3.62 (1H, m), 3.02-2.98 (2H, m), 2.84 (1H, dd, 14.3, 4.9Hz), 2.56-2.48 (1H, m), 1.54 (9H, s)

MS: 482 (M-tBu)⁺

Example 51 tert-butyl5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-2-methoxyphenylcarbamate(compound S1)

NMR (DMSO-d₆): δ8.32-8.30 (2H, m), 7.81 (1H, br), 7.59 (1H, dd, 8.7, 2.3Hz), 7.26-7.21 (3H, m), 6.97 (1H, d, 8.9 Hz), 4.85 (1H, d, 17.4 Hz),4.50 (1H, d, 17.4 Hz), 3.91 (3H, s), 3.75 (3H, s), 3.69-3.60 (1H, m),3.01-2.96 (2H, m), 2.83 (1H, dd, 14.2, 4.6 Hz), 2.55-2.49 (1H, m), 1.48(9H, s)

MS: 512 (M-tBu)⁺

Example 52 tert-butyl5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-2-methylphenylcarbamate(compound S2)

NMR (DMSO-d₆): δ8.83 (1H, s), 8.01 (1H, m), 7.82 (1H, br), 7.51 (1H, dd,8.0, 1.8 Hz), 7.42 (1H, d, 8.0 Hz), 7.27-7.23 (2H, m), 6.97 (1H, d, 9.5Hz), 4.86 (1H, d, 17.5 Hz), 4.50 (1H, d, 17.5 Hz), 3.74 (3H, s),3.69-3.60 (1H, m), 3.03-2.93 (2H, m), 2.83 (1H, dd, 14.3, 4.6 Hz),2.55-2.48 (1H, m), 2.29 (3H, s), 1.49 (9H, s)

MS: 496 (M-tBu)⁺

Example 533-({1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-6-yl}methyl)benzonitrile(compound S3)

NMR (CDCl₃): δ7.95 (2H, d, 8.7 Hz), 7.58-7.51 (3H, m), 7.47-7.38 (3H,m), 5.79 (1H, br), 5.01 (1H, d, 17.7 Hz), 4.41 (1H, d, 17.7 Hz),3.42-3.18 (4H, m), 2.60 (1H, dd, 14.5, 7.5 Hz)

MS: 418 (M+H)⁺

Example 544-[(4-chlorophenyl)sulfonyl]-6-[2-methoxy-5-(trifluoromethyl)benzyl]-1,4-diazepan-2,5-dione(compound 54)

NMR (CDCl₃): δ7.97 (2H, d, J=8.7 Hz), 7.52 (3H, d, J=8.7 Hz), 7.31 (1H,s), 6.92 (1H, d, J=8.6 Hz), 5.70-5.64 (1H, br), 5.02 (1H, d, J=17.7 Hz),4.39 (1H, d, J=17.7 Hz), 3.88 (3H, s), 3.48-3.40 (1H, m), 3.26-3.15 (3H,m), 2.61 (1H, dd, J=14.2, 8.9 Hz)

MS: 491 (M+H)⁺

Example 55N-(2-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}phenyl)-N∝-ethylurea(compound S5)

NMR (CDCl₃): δ8.59 (1H, d, J=2.1 Hz), 7.66 (1H, dd, J=8.5, 2.1 Hz), 7.49(1H, d, J=8.5 Hz), 7.17 (1H, dd, J=8.8, 2.5 Hz), 7.00 (1H, d, J=2.5 Hz),6.85 (1H, s), 6.76 (1H, d, J=8.8 Hz), 5.99 (1H, br), 5.06-4.99 (2H, m),4.44 (1H, d, J=17.9 Hz), 3.80 (3H, s), 3.54-3.45 (1H, m), 3.38-3.18 (4H,m), 3.10 (1H, dd, J=14.1, 4.7 Hz), 2.47 (1H, dd, J=14.1, 9.0 Hz), 1.21(3H, t, J=7.2 Hz)

MS: 543 (M+H)⁺

Example 564-[(4-chlorobenzyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound S6)

NMR (CDCl₃): δ7.28-7.13 (6H, m), 6.83 (1H, d, J=8.7 Hz), 5.82-5.76 (1H,br), 4.80 (1H, d, J=14.0 Hz), 4.70 (1H, d, J=14.0 Hz), 4.38 (1H, d,J=18.0 Hz), 3.84 (3H, s), 3.69 (1H, d, J=18.0 Hz), 3.40-3.29 (3H, m),3.26-3.16 (1H, m), 2.62 (1H, dd, J=13.9, 7.6 Hz)

MS: 471 (M+H)⁺

Example 574-[(4-chlorophenyl)sulfonyl]-6-(5-hydroxy-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound S7)

NMR (CDCl₃): δ7.97 (2H, d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz), 6.73 (1H,d, J=8.7 Hz), 6.69 (1H, dd, J=8.7, 2.8 Hz), 6.58 (1H, d, J=2.8 Hz),5.63-5.58 (1H, br), 4.97 (1H, d, J=17.7 Hz), 4.59 (1H, s), 4.41 (1H, d,J=17.7 Hz), 3.76 (3H, s), 3.49-3.40 (1H, m), 3.28-3.20 (1H, m),3.17-3.06 (2H, m), 2.53 (1H, dd, J=14.0, 8.9 Hz)

MS: 439 (M+H)⁺

Example 586-(5-chloro-2-methoxybenzyl)-4-{[4-(1H-pyrazol-3-yl)phenyl]sulfonyl}-1,4-diazepan-2,5-dionehydrochloride (compound S8)

NMR (DMSO-d₆): δ8.06 (2H, d, J=8.5 Hz), 7.93 (2H, d, J=8.5 Hz),7.85-7.81 (2H, m, J=2.1 Hz), 7.27-7.21 (2H, m), 6.96 (1H, d, J=9.5 Hz),6.89 (1H, d, J=2.3 Hz), 4.90 (1H, d, J=17.5 Hz), 4.57 (1H, d, J=17.5Hz), 3.74 (3H, s), 3.72-3.64 (1H, m), 3.62-3.58 (1H, m), 3.04-2.94 (2H,m), 2.83 (1H, dd, J=14.3, 4.8 Hz)

MS: 489 (M+H)⁺

Example 594-[(4-chlorophenyl)sulfonyl]-6-[2-(methoxymethoxy)-5-methylbenzyl]-1,4-diazepan-2,5-dione(compound S9)

NMR (CDCl₃): δ7.97 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz), 7.01 (1H,dd, J=8.3, 1.8 Hz), 6.95 (1H, d, J=8.3 Hz), 6.85 (1H, d, J=1.8 Hz),5.80-5.74 (1H, br), 5.16 (1H, d, J=6.6 Hz), 5.14 (1H, d, J=6.6 Hz), 4.99(1H, d, J=17.6 Hz), 4.40 (1H, d, J=17.6 Hz), 3.55-3.40 (1H, m), 3.43(3H, s), 3.30-3.21 (1H, m), 3.19-3.10 (2H, m), 2.57 (1H, dd, J=14.1, 9.5Hz), 2.24 (3H, s)

MS: 489 (M+Na)⁺

Example 60(3S,6R)-6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1,4-diazepan-2,5-dione(compound 60)

NMR (CDCl₃): δ8.02 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.20 (1H,dd, J=8.8, 2.6 Hz), 7.08 (1H, d, J=2.6 Hz), 6.79 (1H, d, J=8.8 Hz),5.95-5.87 (1H, br), 5.12 (1H, q, J=7.4 Hz), 3.81 (3H, s), 3.36-3.21 (4H,m), 2.80 (1H, dd, J=13.2, 8.7 Hz), 1.59 (3H, d, J=7.3 Hz)

MS: 471 (M+H)⁺

Example 61(3R,6S)-6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1,4-diazepan-2,5-dione(compound 61)

NMR (CDCl₃): δ8.02 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.20 (1H,dd, J=8.7, 2.4 Hz), 7.08 (1H, d, J=2.4 Hz), 6.79 (1H, d, J=8.7 Hz), 5.91(1H, br), 5.12 (1H, q, J=7.4 Hz), 3.81 (3H, s), 3.35-3.20 (4H, m), 2.80(1H, dd, J=13.1, 8.6 Hz), 1.59 (3H, d, J=7.4 Hz)

MS: 471 (M+H)⁺

Melting point: 78-80° C.

Example 62 tert-butyl2-(4-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}phenyl)ethylcarbamate(compound 62)

NMR (DMSO-d₆): δ7.85-7.82 (3H, m), 7.45 (2H, d, 8.2 Hz), 7.26-7.23 (2H,m), 6.97 (1H, d, 8.3 Hz), 6.94-6.92 (1H, m), 4.86 (1H, d, 17.5 Hz), 4.53(1H, d, 17.5 Hz), 3.74 (3H, s), 3.70-3.60 (1H, m), 3.22-3.16 (2H, m),2.99-2.95 (2H, m), 2.85-2.78 (3H, m), 2.54-2.47 (1H, m), 1.35 (9H, s)

MS: 466 (M-Boc)⁺

Example 63(3R,6R)-6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1,4-diazepan-2,5-dione(compound 63)

NMR (CDCl₃): δ7.99 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.6 Hz), 7.20 (1H,dd, J=8.8, 2.6 Hz), 6.99 (1H, d, J=2.6 Hz), 6.78 (1H, d, J=8.8 Hz), 5.90(1H, d, J=6.3 Hz), 5.49 (1H, q, J=7.4 Hz), 3.78 (3H, s), 3.40-3.33 (1H,m), 3.29 (1H, d, J=11.7 Hz), 3.22 (1H, dd, J=14.2, 3.7 Hz), 3.06 (1H,dd, J=11.7, 6.9 Hz), 2.38 (1H, dd, J=14.2, 9.4 Hz), 1.65 (3H, d, J=7.4Hz)

MS: 471 (M+H)⁺

Example 646-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-4,8-diazaspiro[2.6]nonan-5,9-dione(compound 64)

NMR (CDCl₃): δ8.02 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.20 (1H,dd, J=8.8, 2.5 Hz), 7.04 (1H, d, J=2.5 Hz), 6.78 (1H, d, J=8.8 Hz), 5.64(1H, br), 4.09-4.00 (1H, m), 3.80 (3H, s), 3.25-3.20 (2H, m), 3.15 (1H,dd, J=14.2, 4.7 Hz), 2.43-2.32 (2H, m), 1.66-1.55 (1H, m), 1.42-1.35(1H, m), 1.15-1.09 (1H, m)

MS: 483 (M+H)⁺

Example 654-[(6-chloro-3-pyridyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 65)

NMR (CDCl₃): δ8.94 (1H, d, J=2.4 Hz), 8.29 (1H, dd, J=8.7, 2.4 Hz), 7.51(1H, d, J=8.7 Hz), 6.92 (1H, dt, J=8.9, 3.1 Hz), 6.81-6.75 (2H, m), 5.83(1H, br), 4.97 (1H, d, J=17.6 Hz), 4.42 (1H, d, J=17.6 Hz), 3.79 (3H,s), 3.55-3.45 (1H, m), 3.27 (1H, dt, J=13.3, 4.3 Hz), 3.19 (1H, dd,J=13.3, 1.5 Hz), 3.10 (1H, dd, J=14.0, 5.1 Hz), 2.57 (1H, dd, J=14.0,8.7 Hz)

MS: 442 (M+H)⁺

Example 664-[(5-chloro-2-thienyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 66)

NMR (CDCl₃): δ7.69 (1H, d, J=4.1 Hz), 6.98-6.87 (2H, m), 6.86-6.72 (2H,m), 5.80-5.73 (1H, br), 4.91 (1H, d, J=17.7 Hz), 4.37 (1H, d, J=17.7Hz), 3.80 (3H, s), 3.51-3.40 (1H, m), 3.28-3.19 (2H, m), 3.19 (1H, dd,J=14.0, 5.0 Hz), 2.63 (1H, dd, J=14.1, 8.8 Hz)

MS: 447 (M+H)³⁰

Example 676-(4-chloro-5-fluoro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 67)

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.53 (2H, d, J=8.7 Hz), 6.89 (1H,d, J=9.0 Hz), 6.50 (1H, d, J=6.1 Hz), 5.71-5.64 (1H, br), 5.01 (1H, d,J=17.7 Hz), 4.39 (1H, d, J=17.7 Hz), 3.80 (3H, s), 3.48-3.38 (1H, m),3.27-3.03 (3H, m), 2.57 (1H, dd, J=14.1, 8.8 Hz)

MS: 475 (M+H)⁺

Melting point: 80-90° C.

Example 684-[(5-chloro-4-fluoro-2-methoxyphenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 68)

NMR (CDCl₃): δ8.20 (1H, d, J=8.0 Hz), 7.21 (1H, dd, J=8.7, 2.6 Hz), 7.02(1H, d, J=2.6 Hz), 6.80 (1H, d, J=10.1 Hz), 6.80 (1H, d, J=8.8 Hz),5.76-5.70 (1H, br), 5.12 (1H, d, J=17.9 Hz), 4.42 (1H, d, J=17.9 Hz),3.87 (3H, s), 3.83 (3H, s), 3.50-3.40 (1H, m), 3.28-3.09 (3H, m), 2.52(1H, dd, J=14.2, 9.3 Hz)

MS: 505 (M+H)³⁰

Example 696-(5-chloro-2-methoxybenzyl)-4-[(2,5-dimethoxyphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 69)

NMR (CDCl₃): δ7.62 (1H, d, J=3.1 Hz), 7.19 (1H, dd, J=8.8, 2.7 Hz), 7.14(1H, dd, J=9.1, 3.1 Hz), 6.99 (1H, d, J=2.7 Hz), 6.93 (1H, d, J=9.1 Hz),6.79 (1H, d, J=8.8 Hz), 5.72-5.68 (1H, br), 5.18 (1H, d, J=18.1 Hz),4.42 (1H, d, J=18.1 Hz), 3.86 (3H, s), 3.83 (3H, s), 3.82 (3H, s),3.51-3.40 (1H, m), 3.22-3.17 (2H, m), 3.12 (1H, dd, J=14.2, 4.4 Hz),2.50 (1H, dd, J=14.2, 9.5 Hz)

MS: 483 (M+H)⁺

Example 706-(5-chloro-2-methoxybenzyl)-4-[(2-methoxy-5-methylphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 70)

NMR (CDCl₃): δ7.93 (1H, d, J=2.0 Hz), 3.39 (1H, dd, J=8.5, 2.0 Hz), 7.19(1H, dd, J=8.7, 2.6 Hz), 6.98 (1H, d, J=2.6 Hz), 6.89 (1H, d, J=8.5 Hz),6.79 (1H, d, J=8.7 Hz), 5.78-5.71 (1H, br), 5.19 (1H, d, J=18.1 Hz),4.41 (1H, d, J=18.1 Hz), 3.84 (3H, s), 3.82 (3H, s), 3.52-3.39 (1H, m),3.20-3.07 (3H, m), 2.49 (1H, dd, J=14.2, 9.4 Hz), 2.38 (3H, s)

MS: 467 (M+H)⁺

Example 716-(5-chloro-2-methoxybenzyl)-4-{[2-methoxy-5-(trifluoromethyl)phenyl]sulfonyl}-1,4-diazepan-2,5-dione(compound 71)

NMR (CDCl₃): δ8.41 (1H, d, J=2.0 Hz), 7.86 (1H, dd, J=8.7, 2.0 Hz), 7.20(1H, dd, J=8.8, 2.7 Hz), 7.10 (1H, d, J=8.8 Hz), 6.99 (1H, d, J=2.7 Hz),6.79 (1H, d, J=8.7 Hz), 5.78-5.71 (1H, br), 5.16 (1H, d, J=18.0 Hz),4.44 (1H, d, J=18.0 Hz), 3.95 (3H, s), 3.83 (3H, s), 3.50-3.40 (1H, m),3.28-3.08 (3H, m), 2.52 (1H, dd, J=14.2, 9.4 Hz)

MS: 521 (M+H)⁺

Example 726-(5-fluoro-2-methoxybenzyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1,4-diazepan-2,5-dione(compound 72)

NMR (CDCl₃): δ8.16 (2H, d, J=8.3 Hz), 7.82 (2H, d, J=8.3 Hz), 6.92 (1H,dt, J=8.8, 3.1 Hz), 6.80-6.75 (2H, m), 5.66 (1H, br), 5.02 (1H, d,J=17.6 Hz), 4.43 (1H, d, J=17.6 Hz), 3.79 (3H, s), 3.53-3.45 (1H, m),3.26 (1H, dt, J=13.3, 4.3 Hz), 3.18 (1H, dd, J=13.3, 1.6 Hz), 3.11 (1H,dd, J=14.0, 4.9 Hz), 2.57 (1H, dd, J=14.0, 8.7 Hz)

MS: 475 (M+H)⁺

Example 736-(5-fluoro-2-methoxybenzyl)-4-[(4-methylphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 73)

NMR (CDCl₃): δ7.91 (2H, d, J=8.3 Hz), 7.34 (2H, d, J=8.3 Hz), 6.96-6.88(1H, m), 6.79-6.74 (2H, m), 5.71-5.65 (1H, br), 5.04 (1H, d, J=17.6 Hz),4.39 (1H, d, J=17.6 Hz), 3.79 (3H, s), 3.52-3.44 (1H, m), 3.28-3.10 (3H,m), 2.53 (1H, dd, J=14.0, 9.0 Hz), 2.45 (3H, s)

MS: 421 (M+H)⁺

Example 744-[(4-aminophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 74)

NMR (CDCl₃): δ7.80 (2H, d, J=8.7 Hz), 6.96-6.87 (1H, m), 6.83-6.72 (2H,m), 6.68 (2H, d, J=8.7 Hz), 5.73-5.69 (1H, br), 5.02 (1H, d, J=17.7 Hz),4.37 (1H, d, J=17.7 Hz), 4.26 (2H, s), 3.79 (3H, s), 3.50-3.37 (1H, m),3.20-3.07 (3H, m), 2.54 (1H, dd, J=14.1, 9.1 Hz)

MS: 422 (M+H)⁺

Example 754-[(4-bromophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 75)

NMR (CDCl₃): δ7.89 (2H, d, J=8.6 Hz), 7.69 (2H, d, J=8.6 Hz), 6.98-6.88(1H, m), 6.82-6.76 (2H, m), 5.81-5.76 (1H, br), 5.00 (1H, d, J=17.8 Hz),4.41 (1H, d, J=17.8 Hz), 3.79 (3H, s), 3.54-3.39 (1H, m), 3.30-3.05 (3H,m), 2.55 (1H, dd, J=14.1, 8.9 Hz)

MS: 485 (M+H)⁺

Example 766-(5-fluoro-2-methoxybenzyl)-4-[(4-fluorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 76)

NMR (CDCl₃): δ8.06 (2H, dd, J=8.8, 4.9 Hz), 7.22 (2H, t, J=8.8 Hz),6.97-6.89 (1H, m), 6.80-6.73 (2H, m), 5.78-5.72 (1H, br), 5.01 (1H, d,J=17.8 Hz), 4.41 (1H, d, J=17.8 Hz), 3.80 (3H, s), 3.53-3.43 (1H, m),3.29-3.23 (1H, m), 3.20-3.10 (2H, m), 2.56 (1H, dd, J=14.0, 8.8 Hz)

MS: 425 (M+H)⁺

Example 776-(5-fluoro-2-methoxybenzyl)-4-[(4-methoxyphenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 77)

NMR (CDCl₃): δ7.97 (2H, d, J=9.0 Hz), 7.00 (2H, d, J=9.0 Hz), 6.94-6.86(1H, m), 6.80-6.72 (2H, m), 5.75-5.70 (1H, br), 5.03 (1H, d, J=17.8 Hz),4.39 (1H, d, J=17.8 Hz), 3.89 (3H, s), 3.79 (3H, s), 3.52-3.40 (1H, m),3.26-3.17 (1H, m), 3.17-3.08 (2H, m), 2.54 (1H, dd, J=14.1, 8.9 Hz)

MS: 437 (M+H)⁺

Example 78 methyl3-{[6-(5-fluoro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}propanoate(compound 78)

NMR (CDCl₃): δ6.99-6.87 (2H, m), 6.84-6.79 (1H, m), 5.80-5.74 (1H, br),4.78 (1H, d, J=17.7 Hz), 4.31 (1H, d, J=17.7 Hz), 3.91 (2H, t, J=7.3Hz), 3.84 (3H, s), 3.73 (3H, s), 3.59-3.48 (1H, m), 3.42-3.19 (3H, m),3.84 (2H, dt, J=7.3, 1.8 Hz), 2.67 (1H, dd, J=14.1, 8.7 Hz)

MS: 417 (M+H)⁺

Example 796-(2-chlorobenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 79)

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.36 (1H,dd, J=5.8, 2.4 Hz), 7.25-7.16 (3H, m), 5.97 (1H, br), 4.99 (1H, d,J=17.7 Hz), 4.41 (1H, d, J=17.7 Hz), 3.57-3.48 (1H, m), 3.34-3.18 (3H,m), 2.72 (1H, dd, J=14.2, 8.2 Hz)

MS: 427 (M+H)⁺

Example 804-[(4-chlorophenyl)sulfonyl]-6-(3,5-dichlorobenzyl)-1,4-diazepan-2,5-dione(compound 80)

NMR (CDCl₃): δ7.95 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.25 (1H,d, J=1.7 Hz), 7.02 (2H, d, J=1.7 Hz), 5.81 (1H, br), 5.02 (1H, d, J=17.8Hz), 4.42 (1H, d, J=17.8 Hz), 3.38-3.13 (4H, m), 2.5 (1H, dd, J=14.4,7.8 Hz)

MS: 461 (M+H)⁺

Example 814-[(4-chlorophenyl)sulfonyl]-6-(2,5-dimethoxybenzyl)-1,4-diazepan-2,5-dione(compound 81)

NMR (CDCl₃): δ7.97 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 6.78-6.71(2H, m), 6.62 (1H, d, J=2.7 Hz), 5.61-5.57 (1H, br), 4.99 (1H, d, J=17.6Hz), 4.41 (1H, d, J=17.6 Hz), 3.76 (3H, s), 3.74 (3H, s), 3.50-3.40 (1H,m), 3.28-3.19 (1H, m), 3.16-3.07 (2H, m), 2.55 (1H, dd, J=14.1, 9.3 Hz)

MS: 453 (M+H)⁺

Example 826-(1,3-benzodioxol-5-ylmethyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 82)

NMR (CDCl₃): δ7.97 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 6.73 (1H,d, J=7.8 Hz), 6.60 (1H, d, J=1.4 Hz), 6.56 (1H, dd, J=7.8, 1.4 Hz), 5.95(2H, s), 5.70-5.63 (1H, br), 4.99 (1H, d, J=17.5 Hz), 4.43 (1H, d,J=17.5 Hz), 3.33-3.19 (2H, m), 3.18-3.08 (2H, m), 2.48 (1H, dd, J=14.4,8.5 Hz)

MS: 437 (M+H)⁺

Example 834-[(4-chlorophenyl)sulfonyl]-6-(2-fluoro-5-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 83)

NMR (CDCl₃): δ7.97 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 6.95 (1H,t, J=9.2 Hz), 6.78-6.70 (1H, m), 6.68-6.61 (1H, m), 5.81-5.76 (1H, br),4.99 (1H, d, J=17.6 Hz), 4.42 (1H, d, J=17.6 Hz), 3.76 (3H, s),3.50-3.33 (1H, m), 3.32-3.11 (3H, m), 2.63 (1H, dd, J=14.4, 8.9 Hz)

MS: 441 (M+H)⁺

Example 846-(5-chloro-2-methoxybenzyl)-N-(4-chlorophenyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 84)

NMR (DMSO-d₆): δ11.08 (1H, s), 7.75 (1H, d, J=3.5 Hz), 7.57 (2H, d,J=8.8 Hz), 7.39 (2H, d, J=8.8 Hz), 7.36 (1H, d, J=2.5 Hz), 7.27 (1H, dd,J=8.8, 2.5 Hz), 7.01 (1H, d, J=8.8 Hz), 4.78 (1H, d, J=17.3 Hz), 4.63(1H, d, J=17.3 Hz), 4.00-3.90 (1H, m), 3.80 (3H, s), 3.23 (1H, t, J=12.9Hz), 3.08-2.99 (2H, m), 2.67 (1H, dd, J=14.4, 9.0 Hz)

MS: 436 (M+H)⁺

Example 856-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-[(1R)-1-phenylethyl]-1,4-diazepan-1-carboxamide(compound 85)

NMR (CDCl₃): δ9.43 (1H, brd, J=7.0 Hz), 7.39-7.30 (4H, m), 7.29-7.25(1H, m), 7.24-7.20 (1H, m), 7.12 (1H, d, J=2.3 Hz), 6.81 (0.5H, d, J=8.8Hz), 6.80 (0.5H, d, J=8.8 Hz), 5.77 (0.5H, br), 5.73 (0.5H, br), 5.41(0.5H, d, J=17.4 Hz), 5.38 (0.5H, d, J=17.4 Hz), 5.10-4.99 (1H, m), 4.12(0.5H, d, J=17.4 Hz), 4.08 (0.5H, d, J=17.4 Hz), 3.83 (1.5H, s), 3.82(1.5H, s), 3.73-3.62 (1H, m), 3.35-3.28 (2H, m), 3.08 (1H, dd, J=14.0,5.1 Hz), 2.64-2.56 (1H, m), 1.55 (1.5H, d, J=7.0 Hz), 1.54 (1.5H, d,J=7.0 Hz)

MS: 430 (M+H)⁺

Example 866-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-[(1S)-1-phenylethyl]-1,4-diazepan-1-carboxamide(compound 86)

NMR (CDCl₃): δ9.44 (1H, brd, J=6.7 Hz), 7.37-7.17 (6H, m), 7.12 (1H, d,J=2.3 Hz), 6.81 (1H, dd, J=8.7, 2.3 Hz), 5.80 (1H, brd, J=15.3 Hz), 5.42(0.5H, d, J=17.4 Hz), 5.39 (0.5H, d, J=17.4 Hz), 5.10-4.98 (1H, m), 4.13(0.5H, d, J=17.4 Hz), 4.08 (0.5H, d, J=17.4 Hz), 3.84 (1.5H, s), 3.83(1.5H, s), 3.72-3.62 (1H, m), 3.33-3.25 (2H, m), 3.19 (1H, dd, J=14.0,5.2 Hz), 2.63-2.53 (1H, m), 1.60-1.48 (3H, m)

MS: 430 (M+H)⁺

Example 876-(5-chloro-2-methoxybenzyl)-N-(5-chloro-2-pyridyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 87)

NMR (DMSO-d₆): δ11.64 (1H, s), 8.37 (1H, d, J=2.3 Hz), 8.01 (1H, d,J=8.9 Hz), 7.95 (1H, dd, J=8.9, 2.3 Hz), 7.75 (1H, d, J=3.4 Hz), 7.35(1H, d, J=2.6 Hz), 7.26 (1H, dd, J=8.8, 2.6 Hz), 7.00 (1H, d, J=8.8 Hz),4.81 (1H, d, J=17.3 Hz), 4.63 (1H, d, J=17.3 Hz), 4.02-3.91 (1H, m),3.79 (3H, s), 3.24 (1H, t, J=12.5 Hz), 3.07-2.94 (2H, m), 2.66 (1H, dd,J=14.0, 8.6 Hz)

MS: 437 (M+H)⁺

Example 886-(5-chloro-2-methoxybenzyl)-4-methyl-3,7-dioxo-N-[(1R)-1-phenylethyl]-1,4-diazepan-1-carboxamide(compound 88)

NMR (DMSO-d₆): δ9.39 (0.5H, d, 6.8 Hz), 9.37 (0.5H, d, 6.4 Hz),7.35-7.29 (5H, m), 7.28-7.24 (2H, m), 7.00-6.97 (1H, m), 4.91-4.84 (2H,m), 4.58 (0.5H, d, 17.1 Hz), 4.55 (0.5H, d, 17.1 Hz), 4.02-3.98 (1H, m),3.78 (3H, s), 3.17-3.09 (1H, m), 2.98 (1H, dd, 15.0, 5.1 Hz), 2.72(1.5H, s), 2.68 (1.5H, s), 2.67-2.58 (2H, m), 1.42 (3H, d, 7.0 Hz)

MS: 444 (M+H)⁺

Example 89N-benzyl-6-(5-chloro-2-methoxybenzyl)-N,4-dimethyl-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 89)

NMR (DMSO-d₆): δ7.40-7.20 (7H, m), 6.98 (1H, d, 8.9 Hz), 4.81-4.12 (3H,m), 4.01-3.85 (1H, m), 3.84-3.65 (1H, m), 3.78 (3H, s), 3.45-3.10 (4H,m), 3.05-2.88 (1H, m), 2.84-2.55 (5H, m)

MS: 444 (M+H)⁺

Reference Example 1344-[(3-amino-4-chlorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound S134)

To the compound 22 (753 mg) in tetrahydrofuran (25 ml) solution, 5%platinum carbon (sulfur poisoned catalyst) (150 mg) was added and themixture was stirred under hydrogen atmosphere at room temperature for 15hours. Next, the catalyst was filtered out and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/3 to 1/2) to obtain the titlecompound (559 mg).

Example 904-[(3-amino-4-chlorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dionehydrochloride (compound 90)

To the compound S134 (438 mg) in chloroform (5 ml) solution, a 4Mhydrogen chloride/1,4-dioxane solution (0.96 ml) was added at roomtemperature, and the precipitated solid was collected by filtration toobtain the title compound (259 mg).

NMR (DMSO-d₆): δ7.85-7.80 (1H, br), 7.44 (1H, d, J=8.3 Hz), 7.40 (1H, d,J=2.3 Hz), 7.28-7.23 (2H, m), 7.00-6.94 (2H, m), 4.86 (1H, d, J=17.5Hz), 4.47 (1H, d, J=17.5 Hz), 3.76 (3H, s), 3.72-3.65 (1H, m), 3.02-2.98(2H, br), 2.85 (1H, dd, J=14.2, 4.2 Hz), 2.55-2.45 (1H, m)

MS: 472 (M+H)⁺

Melting point: 120-122° C.

Reference Example 135{[(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(5-chloro-2-methoxyphenyl)-2-propenyl]amino}ethylacetate (compound S135)

To the compound S23 (123 g) in methylene chloride (400 ml) solution,glycine methyl ester hydrochloride (51 g), 1-hydroxybenzotriazole (49g), triethylamine (53 ml), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 g) wereadded under ice cooling and the mixture was stirred at room temperaturefor 2 hours. The reaction solution was diluted with distilled water,then the precipitate was filtered out and the filtrate was extractedwith ethyl acetate. The organic layer was successively washed withsaturated potassium hydrogensulfate aqueous solution, distilled water,saturated sodium hydrogencarbonate aqueous solution, and saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated. Theresidue was recrystallized from hexane/ethyl acetate to obtain the titlecompound (131.5 g).

Reference Example 136{[(2E)-2-(aminomethyl)-3-(5-chloro-2-methoxyphenyl)-2-propenyl]amino}ethylacetate hydrochloride (compound S136)

A mixed solution of the compound S135 (131.5 g) and a 4M hydrogenchloride/ethyl acetate solution (350 ml) was stirred at room temperaturefor 20 minutes. The reaction solution was diluted with diethylether,then the precipitate was collected by filtration to obtain the titlecompound (109.3 g).

Reference Example 137[((2E)-3-(5-chloro-2-methoxyphenyl)-2-{[(2,4,6-trimethoxybenzyl)amino]methyl}-2-propenyl)amino]ethylacetate hydrochloride (compound S137)

To the compound S136 (55.8 g) in tetrahydrofuran (800 ml) solution,2,4,6-trimethoxybenzaldehyde (30.5 g) was added and the mixture wasstirred at room temperature for 20 minutes. Next, sodium triacetoxyborohydride (50 g) was added to the reaction solution and the mixturewas stirred at room temperature for 1 hour. Distilled water was added tothe reaction solution, then tetrahydrofuran was distilled off in vacuo.The remaining aqueous layer was basified by a sodium hydroxide aqueoussolution, then the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline, dried over with anhydrous sodiumsulfate, and partially distilled off in vacuo. A 4M hydrogenchloride/ethyl acetate solution was added to the remaining solution andthe mixture was stirred under ice cooling for 30 minutes. Theprecipitate was collected by filtration to obtain the title compound(75.7 g).

NMR (DMSO-d₆): δ9.12 (1H, br), 8.58 (1H, br), 7.59 (1H, s), 7.48 (1H, d,J=8.9 Hz), 7.32 (1H, s), 7.13 (1H, d, J=8.9 Hz), 6.23 (2H, s), 4.13 (2H,q, J=7.1 Hz), 3.96 (2H, d, J=5.7 Hz), 3.84-3.70 (16H, m), 1.21 (3H, t,J=7.1 Hz)

Reference Example 138[((2E)-3-(5-chloro-2-methoxyphenyl)-2-{[(2,4,6-trimethoxybenzyl)amino]methyl}-2-propenyl)amino]aceticacid hydrochloride (compound S138)

To the compound S137 (148.5 g) in methanol (300 ml) solution, 2N sodiumhydroxide aqueous solution (300 ml) was added and the mixture wasstirred at room temperature for 2 hours. The reaction solution wasneutralized by 6M hydrochloric acid (100 ml), then the methanol wasdistilled off in vacuo. Crystal nuclei were added to the remainingsolution and the mixture was stirred under ice cooling for 30 minutes.The precipitate was collected by filtration to obtain the title compoundas a crude product (143.1 g).

Reference Example 139(6E)-6-(5-chloro-2-methoxybenzylidene)-1-(2,4,6-trimethoxybenzyl)-1,4-diazepan-2,5-dione(compound S139)

A solution of the compound S138 (53 g) and 1-hydroxybenzotriazole (14 g)in N,N-dimethylformamide (1000 ml) was added dropwise to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24 g) andtriethylamine (17 ml) in N,N-dimethylformamide (500 ml) over 2 hours.After dropping, the insoluble compound was filtered out, then thefiltrate was concentrated. Ethyl acetate and 1N hydrochloric acid wereadded to the residue and the mixture was stirred for 30 minutes. Theinsoluble compound was collected by filtration and washed with distilledwater and ethyl acetate. Ethyl acetate and 1N sodium hydroxide aqueoussolution were added to the obtained solid and stirred for 30 minutes.The insoluble compound was collected by filtration and washed withdistilled water and ethyl acetate. A mixed solvent oftetrahydrofuran/methanol=1/1 was added to the obtained solid and themixture was stirred under heating and reflux for 30 minutes. Thesolution was allowed to cool to room temperature, then the mixedsolution was filtered by sellite and the filtrate was concentrated. Theresidue was recrystallized from ethyl acetate to obtain the titlecompound (22.1 g).

NMR (CDCl₃): δ7.6 (1H, s), 7.29-7.19 (1H, m), 6.76-6.69 (2H, m), 6.05(1H, br), 5.75 (2H, s), 4.52 (2H, s), 4.23 (2H, s), 4.05 (2H, d, J=6.1Hz), 3.80-3.74 (6H, m), 3.52 (6H, s)

Reference Example 1406-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,4-diazepan-2,5-dione(compound S140A),(6S)-6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,4-diazepan-2,5-dione(compound S140B), and(6R)-6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,4-diazepan-2,5-dione(compound S140C)

To the compound S139 (16.3 g) in tetrahydrofuran (600 ml) solution, 2%platinum carbon (sulfur poisoned catalyst) (7.3 g) was added and themixture was stirred under hydrogen atmosphere at room temperature for 60hours. Next, the catalyst was filtered out and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (chloroform/ethyl acetate/methanol=7/1/0.5) to obtain thetitle compound (compound S140A) (13.1 g).

The compound S140A was separated using CHIRALCEL OD-H (Daicel ChemicalIndustries) (movement phase: acetonitrile/trifluoroacetic acid=100/0.1)to obtain the compound S140B and the compound S140C.

(Compound S140A)

NMR (CDCl₃): δ7.14 (1H, dd, J=8.7, 2.5 Hz), 6.88 (1H, d, J=2.5 Hz), 6.69(1H, d, J=8.7 Hz), 5.98 (2H, s), 5.94 (1H, br), 4.8 (1H, d, J=13.7 Hz),4.30-4.20 (2H, m), 3.83 (3H, s), 3.78-3.69 (4H, m), 3.63 (6H, s), 3.38(1H, dd, J=15.4, 12.2 Hz), 3.11 (1H, dd, J=13.0, 3.2 Hz), 2.94 (1H, dd,J=15.4, 4.9 Hz), 2.5 (1H, dd, J=13.0, 10.7 Hz)

(Compound S140B)

NMR (CDCl₃): δ7.14 (1H, dd, J=8.7, 2.5 Hz), 6.88 (1H, d, J=2.5 Hz), 6.69(1H, d, J=8.7 Hz), 5.98 (2H, s), 5.94 (1H, br), 4.8 (1H, d, J=13.7 Hz),4.30-4.20 (2H, m), 3.83 (3H, s), 3.78-3.69 (4H, m), 3.63 (6H, s), 3.38(1H, dd, J=15.4, 12.2 Hz), 3.11 (1H, dd, J=13.0, 3.2 Hz), 2.94 (1H, dd,J=15.4, 4.9 Hz), 2.5 (1H, dd, J=13.0, 10.7 Hz)

(Compound S140C)

NMR (CDCl₃): δ7.14 (1H, dd, J=8.7, 2.5 Hz), 6.88 (1H, d, J=2.5 Hz), 6.69(1H, d, J=8.7 Hz), 5.98 (2H, s), 5.94 (1H, br), 4.8 (1H, d, J=13.7 Hz),4.30-4.20 (2H, m), 3.83 (3H, s), 3.78-3.69 (4H, m), 3.63 (6H, s), 3.38(1H, dd, J=15.4, 12.2 Hz), 3.11 (1H, dd, J=13.0, 3.2 Hz), 2.94 (1H, dd,J=15.4, 4.9 Hz), 2.5 (1H, dd, J=13.0, 10.7 Hz)

Reference Example 141A 2-chlorophenyl6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate(compound S141A)

To the compound S140A (4.07 g) in tetrahydrofuran (200 ml) solution, a1.59M hexane solution of n-butyllithium (6 ml) was added at −78° C. andthe mixture was stirred at that temperature for 20 minutes. Next,2-chlorophenyl chlorocarbonate (1.4 ml) was added to the reactionsolution at −78° C. and the mixture was stirred at that temperature for20 minutes. The reaction solution was diluted with saturated potassiumhydrogensulfate aqueous solution and distilled water, and the mixturewas extracted with ethyl acetate. The organic layer was successivelywashed with saturated saline and distilled water, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate/methanol=1/2/0 to3/3/1) to obtain the title compound (4.21 g).

NMR (CDCl₃): δ7.44-7.40 (1H, m), 7.33-7.12 (4H, m), 6.93 (1H, d, J=2.6Hz), 6.73 (1H, d, J=8.8 Hz), 6.05 (2H, s), 5.06 (1H, d, J=17.6 Hz), 4.83(1H, d, J=13.7 Hz), 4.44 (1H, d, J=17.6 Hz), 4.34 (1H, d, J=13.7 Hz),3.83 (3H, s), 3.77 (3H, s), 3.7 (6H, s), 3.57-3.45 (1H, m), 3.29-3.14(2H, m), 3.07 (1H, dd, J=14.1, 3.8 Hz), 2.38 (1H, dd, J=14.1, 9.8 Hz)

Reference Example 141B (6S)-2-chlorophenyl6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate(compound S141B)

Instead of the starting material compound of Reference Example 141A,that is, the compound S140A, the compound S140B was used for the similarprocedure as in Reference Example 141A to obtain the title compound.

NMR (CDCl₃): δ7.44-7.40 (1H, m), 7.33-7.12 (4H, m), 6.93 (1H, d, J=2.6Hz), 6.73 (1H, d, J=8.8 Hz), 6.05 (2H, s), 5.06 (1H, d, J=17.6 Hz), 4.83(1H, d, J=13.7 Hz), 4.44 (1H, d, J=17.6 Hz), 4.34 (1H, d, J=13.7 Hz),3.83 (3H, s), 3.77 (3H, s), 3.7 (6H, s), 3.57-3.45 (1H, m), 3.29-3.14(2H, m), 3.07 (1H, dd, J=14.1, 3.8 Hz), 2.38 (1H, dd, J=14.1, 9.8 Hz)

Reference Example 141C (6R)-2-chlorophenyl6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate(compound S141C)

Instead of the starting material compound of Reference Example 141A,that is, the compound S140A, the compound S140C was used for the similarprocedure as in Reference Example 141A to obtain the title compound.

NMR (CDCl₃): δ7.44-7.40 (1H, m), 7.33-7.12 (4H, m), 6.93 (1H, d, J=2.6Hz), 6.73 (1H, d, J=8.8 Hz), 6.05 (2H, s), 5.06 (1H, d, J=17.6 Hz), 4.83(1H, d, J=13.7 Hz), 4.44 (1H, d, J=17.6 Hz), 4.34 (1H, d, J=13.7 Hz),3.83 (3H, s), 3.77 (3H, s), 3.7 (6H, s), 3.57-3.45 (1H, m), 3.29-3.14(2H, m), 3.07 (1H, dd, J=14.1, 3.8 Hz), 2.38 (1H, dd, J=14.1, 9.8 Hz)

Reference Example 142A tert-butyl3-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound S142A) and tert-butyl3-{(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound S142B)

To the compound S141A (3 g) in N,N-dimethylformamide (6 ml) solution,4-dimethylaminopyridine was added under ice cooling and the mixture wasstirred at that temperature for 30 minutes. Next, the compound S83 (2 g)and triethylamine (1.6 ml) were added to the reaction solution and themixture was stirred under ice cooling for 14 hours. The reactionsolution was diluted with ethyl acetate, then was successively washedwith distilled water, saturated potassium hydrogensulfate aqueoussolution, and saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=2/3 to 1/2) to obtain thetitle compound (compound S142A) (1.21 g) and the title compound(compound S142B) (1.34 g).

(Compound S142A)

NMR (CDCl₃): δ9.49 (1H, d, J=7.3 Hz), 7.89 (1H, s), 7.85 (1H, d, J=7.6Hz), 7.43 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.6 Hz), 7.16 (1H, dd,J=8.8, 2.6 Hz), 6.89 (1H, d, J=2.6 Hz), 6.73 (1H, d, J=8.8 Hz), 6.06(2H, s), 5.28 (1H, d, J=17.4 Hz), 4.82 (1H, q, J=7.3 Hz), 4.76 (1H, d,J=13.8 Hz), 4.31 (1H, d, J=13.8 Hz), 4.19 (1H, d, J=17.4 Hz), 3.82 (3H,s), 3.76 (3H, s), 3.69 (6H, s), 3.57-3.43 (1H, m), 3.1 (1H, dd, J=14.0,4.4 Hz), 3.05-2.96 (2H, m), 2.37 (1H, dd, J=14.0, 9.6 Hz), 1.90-1.78(2H, m), 1.57 (9H, s), 0.89 (3H, t, J=7.3 Hz)

(Compound S142B)

NMR (CDCl₃): δ9.48 (1H, d, J=7.5 Hz), 7.92-7.88 (2H, m), 7.43 (1H, d,J=7.7 Hz), 7.36 (1H, t, J=7.7 Hz), 7.18 (1H, dd, J=8.7, 2.6 Hz), 6.92(1H, d, J=2.6 Hz), 6.75 (1H, d, J=8.7 Hz), 5.99 (2H, s), 5.29 (1H, d,J=17.4 Hz), 4.85 (1H, q, J=7.5 Hz), 4.76 (1H, d, J=13.8 Hz), 4.257 (1H,d, J=13.8 Hz), 4.252 (1H, d, J=17.4 Hz), 3.81 (3H, s), 3.77 (3H, s),3.60-3.48 (1H, m), 3.54 (6H, s), 3.1 (1H, dd, J=13.8, 4.8 Hz), 3.00-2.94(2H, m), 2.4 (1H, dd, J=13.8, 9.2 Hz), 1.94-1.76 (2H, m), 1.6 (9H, s),0.9 (3H, t, J=7.5 Hz)

Reference Example 142B tert-butyl3-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound S142A)

To the compound S142B (400 mg) in N,N-dimethylformamide (3 ml) solution,1,8-diazabicyclo[5.4.0]undeca-7-ene was added and the mixture wasstirred at room temperature for 24 hours. The reaction solution wasdiluted with ethyl acetate, then was successively washed saturatedpotassium hydrogensulfate aqueous solution, distilled water, andsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate-1/1 to 2/3) to obtain the titlecompound (163 mg) and, as a recovered starting material, the compoundS142B (200 mg).

NMR (CDCl₃): δ9.49 (1H, d, J=7.3 Hz), 7.89 (1H, s), 7.85 (1H, d, J=7.6Hz), 7.43 (1H, d, J=7.6 Hz), 7.35 (1H, t, J=7.6 Hz), 7.16 (1H, dd,J=8.8, 2.6 Hz), 6.89 (1H, d, J=2.6 Hz), 6.73 (1H, d, J=8.8 Hz), 6.06(2H, s), 5.28 (1H, d, J=17.4 Hz), 4.82 (1H, q, J=7.3 Hz), 4.76 (1H, d,J=13.8 Hz), 4.31 (1H, d, J=13.8 Hz), 4.19 (1H, d, J=17.4 Hz), 3.82 (3H,s), 3.76 (3H, s), 3.69 (6H, s), 3.57-3.43 (1H, m), 3.1 (1H, dd, J=14.0,4.4 Hz), 3.05-2.96 (2H, m), 2.37 (1H, dd, J=14.0, 9.6 Hz), 1.90-1.78(2H, m), 1.57 (9H, s), 0.89 (3H, t, J=7.3 Hz)

Example 913-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 91)

To the compound S142A (1.92 g), 1M hydrogen chloride/acetic acidsolution (15 ml) was added and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was concentrated, thenthe residue was successively purified by silica gel columnchromatography (chloroform/ethyl acetate/methanol/aceticacid=8/8/1/0.08), silica gel column chromatography (hexane/ethylacetate/methanol/acetic acid=5/5/1/0.1), and florisil columnchromatography (ethyl acetate/isopropanol, isopropanol: 0 to 20%).Hexane was added to the obtained purified product in ethyl acetatesolution, then the precipitated solid was collected by filtration toobtain the title compound (0.5 g).

NMR (DMSO-d₆): δ13.01 (1H, br), 9.48 (1H, d, J=7.3 Hz), 7.86 (1H, s),7.82 (1H, d, J=7.7 Hz), 7.67 (1H, d, J=3.5 Hz), 7.55 (1H, d, J=7.7 Hz),7.46 (1H, t, J=7.7 Hz), 7.33 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.8, 2.6Hz), 7.00 (1H, d, J=8.8 Hz), 4.79-4.69 (2H, m), 4.49 (1H, d, J=17.2 Hz),3.91-3.81 (1H, m), 3.79 (3H, s), 3.16 (1H, t, J=12.6 Hz), 3.05-2.96 (2H,m), 2.67 (1H, dd, J=14.3, 9.3 Hz), 1.89-1.74 (2H, m), 0.84 (3H, t, J=7.3Hz)

MS: 488 (M+H)⁺

Instead of the starting material compound of Reference Example 142A,that is, the compound S83, the amine derivatives of Table VII to TableIX were used for the similar procedure as with Reference Example 142Aand Example 91 to obtain the title compounds of Examples 92 to 149. Notethat the amine derivatives shown in Table VII to Table IX are compoundsshown in the reference examples and also commercially availablecompounds or compounds obtained by derivation from commerciallyavailable compounds by known methods.

TABLE VII Amine derivative Ex. no. used as material Ex. 92

Ex. 93

Ex. 94

Ex. 95

Ex. 96

Ex. 97

Ex. 98

Ex. 99

Ex. 100

Ex. 101

Ex. 102

Ex. 103

Ex. 104

Ex. 105

Ex. 106

Ex. 107

Ex. 108

Ex. 109

Ex. 110

Ex. 111

TABLE VIII Amine derivative Ex. no. used as material Ex. 112

Ex. 113 Compound S86 Ex. 114 Compound S86 Ex. 115

Ex. 116

Ex. 117

Ex. 118 Compound S87 Ex. 119

Ex. 120 Compound S74 Ex. 121 Compound S87 Ex. 122 Compound S109 Ex. 123Compound S109 Ex. 124 Compound S84 Ex. 125 Compound S83 Ex. 126 CompoundS84 Ex. 127 Compound S112 Ex. 128 Compound S113 Ex. 129 Compound S113Ex. 130 Compound S78 Ex. 131 Compound S90

TABLE IX Amine derivative Ex. no. used as material Ex. 132 Compound S90Ex. 133 Compound S91 Ex. 134 Compound S91 Ex. 135 Compound S110 Ex. 136Compound S111 Ex. 137 Compound S92 Ex. 138 Compound S93 Ex. 139 CompoundS79 Ex. 140 Compound S77 Ex. 141 Compound S77 Ex. 142 Compound S114 Ex.143 Compound S114 Ex. 144 Compound S80 Ex. 145 Compound S80 Ex. 146Compound S81 Ex. 147 Compound S81 Ex. 148 Compound S85 Ex. 149 CompoundS78

Example 92(2S)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)-3-phenylpropanoicacid (compound 92)

NMR (DMSO-d₆): δ13.04 (1H, br), 9.31 (0.5H, d, 7.7 Hz), 9.27 (0.5H, d,6.8 Hz), 7.67 (1H, br), 7.34-7.20 (5H, m), 7.19-7.10 (2H, m), 6.99 (1H,d, 8.8 Hz), 4.76 (0.5H, d, 17.3 Hz), 4.75 (0.5H, d, 17.4 Hz), 4.59-4.49(2H, m), 3.90-3.81 (1H, m), 3.77 (3H, s), 3.19-2.99 (4H, m), 2.98-2.85(1H, m), 2.68-2.55 (1H, m)

MS: 474 (M+H)⁺

Example 93(2S)-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)(phenyl)aceticacid (compound 93)

NMR (DMSO-d₆): δ13.25 (1H, br), 9.96 (0.5H, d, 6.3 Hz), 9.88 (0.5H, d,6.3 Hz), 7.69 (0.5H, br), 7.65 (0.5H, br), 7.45-7.30 (6H, m), 7.26 (1H,d, 8.8 Hz), 6.99 (1H, d, 8.8 Hz), 5.29 (1H, d, 6.3 Hz), 4.77 (0.5H, d,17.2 Hz), 4.74 (0.5H, d, 17.2 Hz), 4.54 (0.5H, d, 17.2 Hz), 4.50 (0.5H,d, 17.2 Hz), 3.95-3.85 (1H, m), 3.78 (3H, s), 3.19-2.90 (3H, m),2.69-2.59 (1H, m)

MS: 460 (M+H)⁺

Example 94N-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}-3-phenyl-β-alanine(compound 94)

NMR (DMSO-d₆): δ12.54-12.00 (1H, br), 9.71 (0.5H, d, 8.1 Hz), 9.66(0.5H, d, 8.1 Hz), 7.69-7.60 (1H, m), 7.40-7.18 (7H, m), 6.99 (1H, d,8.7 Hz), 5.22-5.13 (1H, m), 4.77 (0.5H, d, 17.1 Hz), 4.75 (0.5H, d, 17.1Hz), 4.52 (0.5H, d, 17.1 Hz), 4.48 (0.5H, d, 17.1 Hz), 3.93-3.82 (1H,m), 3.78 (3H, s), 3.15-3.07 (1H, m), 3.05-2.92 (2H, m), 2.91-2.75 (2H,m), 2.69-2.58 (1H, m)

MS: 474 (M+H)⁺

Example 95N-benzhydryl-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 95)

NMR (CDCl₃): δ9.93 (1H, d, 7.9 Hz), 7.40-7.15 (10H, m), 7.22 (1H, dd,8.8, 2.5 Hz), 7.12 (1H, d, 2.5 Hz), 6.81 (1H, d, 8.8 Hz), 6.20 (1H, d,7.9 Hz), 5.70 (1H, br), 5.42 (1H, d, 17.6 Hz), 4.13 (1H, d, 17.6 Hz),3.83 (3H, s), 3.78-3.64 (1H, m), 3.38-3.25 (2H, m), 3.19 (1H, dd, 13.9,5.1 Hz), 2.60 (1H, dd, 13.9, 8.5 Hz)

MS: 492 (M+H)⁺

Example 966-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-(1-phenylpropyl)-1,4-diazepan-1-carboxamide(compound 96)

NMR (CDCl₃): δ9.49 (1H, brd, 7.7 Hz), 7.39-7.21 (6H, m), 7.13 (1H, d,2.5 Hz), 6.81 (0.5H, d, 8.7 Hz), 6.80 (0.5H, d, 8.8 Hz), 5.64 (0.5H,br), 5.60 (0.5H, br), 5.40 (0.5H, d, 17.6 Hz), 5.38 (0.5H, d, 17.6 Hz),4.85-4.76 (1H, m), 4.12 (0.5H, d, 17.6 Hz), 4.07 (0.5H, d, 17.6 Hz),3.84 (1.5H, s), 3.82 (1.5H, s), 3.72-3.62 (1H, m), 3.35-3.27 (2H, m),3.19 (1H, dd, 13.9, 5.2 Hz), 2.65-2.59 (1H, m), 1.95-1.79 (2H, m),0.95-0.86 (3H, m)

MS: 444 (M+H)⁺

Example 976-(5-chloro-2-methoxybenzyl)-N-[1-(1-naphthyl)ethyl]-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 97)

NMR (CDCl₃): δ9.54 (0.5H, d, 6.9 Hz), 9.52 (0.5H, d, 6.3 Hz), 8.14 (1H,d, 8.4 Hz), 7.87 (1H, d, 8.0 Hz), 7.79 (1H, t, 7.8 Hz), 7.59-7.45 (4H,m), 7.25-7.19 (1H, m), 7.10 (1H, s), 6.81 (0.5H, d, 8.8 Hz), 6.79 (0.5H,d, 8.8 Hz), 5.95-5.84 (1H, m), 5.68 (0.5H, br), 5.62 (0.5H, br), 5.46(0.5H, 17.7 Hz), 5.42 (0.5H, d, 17.7 Hz), 4.15 (0.5H, d, 17.7 Hz), 4.10(0.5H, d, 17.7 Hz), 3.83 (1.5H, s), 3.81 (1.5H, s), 3.73-3.65 (1H, m),3.35-3.30 (1H, m), 3.29-3.24 (1H, m), 3.16 (1H, dd, 13.9, 5.0 Hz),2.62-2.55 (1H, m), 1.70 (3H, d, 6.8 Hz)

MS: 480 (M+H)⁺

Example 986-(5-chloro-2-methoxybenzyl)-N-(1,2-diphenylethyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 98)

NMR (CDCl₃): δ9.63-9.56 (1H, m), 7.35-7.12 (11H, m), 7.09-7.07 (1H, m),6.81 (0.5H, d, 8.7 Hz), 6.80 (0.5H, d, 8.7 Hz), 5.70-5.65 (1H, m), 5.33(0.5H, d, 17.6 Hz), 5.32 (0.5H, d, 17.6 Hz), 5.19-5.11 (1H, m), 4.05(0.5H, d, 17.6 Hz), 4.04 (0.5H, d, 17.6 Hz), 3.83 (1.5H, s), 3.82 (1.5H,s), 3.70-3.60 (1H, m), 3.33-3.25 (2H, m), 3.22-3.05 (3H, m), 2.65-2.55(1H, m)

MS: 506 (M+H)⁺

Example 996-(5-chloro-2-methoxybenzyl)-N-(2-methoxyphenyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 99)

NMR (DMSO-d₆): δ11.55 (1H, s), 8.12 (1H, d, J=7.7 Hz), 7.71 (1H, d,J=3.5 Hz), 7.36 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.8, 2.6 Hz),7.08-7.04 (2H, m), 7.01 (1H, d, J=8.8 Hz), 6.98-6.92 (1H, m), 4.90 (1H,d, J=17.3 Hz), 4.60 (1H, d, J=17.3 Hz), 4.00-3.91 (1H, m), 3.87 (3H, s),3.80 (3H, s), 3.19 (1H, t, J=12.8 Hz), 3.07-2.99 (2H, m), 2.69 (1H, dd,J=14.3, 9.1 Hz)

MS: 432 (M+H)⁺

Example 100(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propanoicacid (compound 100)

NMR (CDCl₃): δ9.45-9.40 (1H, m), 7.23-7.19 (1H, m), 7.15 (0.5H, d, 2.3Hz), 7.12 (0.5H, d, 2.4 Hz), 6.99 (0.5H, br), 6.81 (0.5H, d, 8.8 Hz),6.80 (0.5H, d, 8.8 Hz), 6.57 (0.5H, br), 5.32 (0.5H, d, 17.3 Hz), 5.29(0.5H, d, 17.3 Hz), 4.55-4.45 (1H, m), 4.17 (0.5H, d, 17.3 Hz), 4.15(0.5H, d, 17.3 Hz), 3.84 (3H, s), 3.75-3.65 (1H, m), 3.40-3.30 (2H, m),3.25-3.15 (1H, m), 2.68-2.57 (1H, m), 1.52 (1.5H, d, 7.2 Hz), 1.49(1.5H, d, 7.3 Hz)

MS: 398 (M+H)⁺

Example 1016-(5-chloro-2-methoxybenzyl)-N-[(1S)-2-hydroxy-1-phenylethyl]-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 101)

NMR (CDCl₃): δ9.75 (0.5H, d, 7.5 Hz), 9.73 (0.5H, d, 7.5 Hz). 7.42-7.30(5H, m), 7.22 (1H, dd, 8.7, 2.5 Hz), 7.15 (1H, d, 2.5 Hz), 6.82 (0.5H,d, 8.7 Hz), 6.81 (0.5H, d, 8.7 Hz), 5.73 (0.5H, br), 5.69 (0.5H, br),5.38 (1H, d, 17.7 Hz), 5.29-5.21 (1H, m), 4.43-4.28 (2H, m), 4.14 (0.5H,d, 17.7 Hz), 4.10 (0.5H, d, 17.7 Hz), 3.84 (1.5H, s), 3.83 (1.5H, s),3.74-3.67 (1H, m), 3.39-3.30 (2H, m), 3.20 (1H, dd, 13.9, 5.1 Hz),2.69-2.60 (1H, m)

MS: 446 (M+H)⁺

Example 102N-benzyl-6-(5-chloro-2-methoxybenzyl)-N-methyl-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 102)

NMR (CDCl₃): δ7.42-7.25 (5H, m), 7.20 (1H, dd, 8.7, 2.5 Hz), 7.13 (1H,m), 6.80 (1H, d, 8.7 Hz), 5.85-5.75 (1H, m), 4.80-4.19 (4H, m), 3.84(3H, s), 3.49-3.38 (1H, m), 3.37-3.20 (2H, m), 3.05-2.79 (4H, m),2.70-2.55 (1H, m)

MS: 430 (M+H)⁺

Example 103N-benzyl-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 103)

NMR (CDCl₃): δ9.37 (1H, br), 7.39-7.29 (5H, m), 7.21 (1H, dd, 8.7, 2.6Hz), 7.11 (1H, d, 2.6 Hz), 6.80 (1H, d, 8.7 Hz), 5.76 (1H, br), 5.45(1H, d, 17.5 Hz), 4.51 (2H, d, 5.5 Hz), 4.14 (1H, d, 17.5 Hz), 3.83 (3H,s), 3.75-3.68 (1H, m), 3.36-3.31 (2H, m), 3.16 (1H, dd, 13.9, 5.4 Hz),2.58 (1H, dd, 13.9, 8.2 Hz)

MS: 416 (M+H)⁺

Example 1046-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-(2-phenylethyl)-1,4-diazepan-1-carboxamide(compound 104)

NMR (CDCl₃): δ9.06 (1H, br), 7.36-7.21 (6H, m), 7.13 (1H, d, 2.6 Hz),6.80 (1H, d, 8.7 Hz), 5.72 (1H, br), 5.41 (1H, d, 17.4 Hz), 4.10 (1H, d,17.4 Hz), 3.83 (3H, s), 3.75-3.65 (1H, m), 3.64-3.52 (2H, m), 3.38-3.27(2H, m), 3.14 (1H, dd, 13.9, 5.7 Hz), 2.88 (2H, t, 7.3 Hz), 2.59 (1H, d,13.9, 7.9 Hz)

MS: 430 (M+H)⁺

Example 1056-(5-chloro-2-methoxybenzyl)-N-[(1R)-1-cyclohexylethyl]-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 105)

NMR (CDCl₃): δ8.98 (1H, d, 8.2 Hz), 7.21 (1H, dd, 8.8, 2.6 Hz), 7.13(0.5H, d, 2.6 Hz), 7.12 (0.5H, d, 2.6 Hz), 6.81 (1H, d, 8.8 Hz), 5.74(1H, br), 5.43 (1H, d, 17.6 Hz), 5.11 (1H, d, 17.6 Hz), 3.84 (1.5H, s),3.83 (1.5H, s), 3.82-3.75 (1H, m), 3.72-3.64 (1H, m), 3.35-3.30 (2H, m),3.22-3.17 (1H, m), 2.60 (1H, dd, 14.0, 8.5 Hz), 1.81-1.65 (5H, m),1.48-0.85 (6H, m), 1.15 (1.5H, d, 5.7 Hz), 1.13 (1.5H, d, 5.6 Hz)

MS: 436 (M+H)⁺

Example 1066-(5-chloro-2-methoxybenzyl)-N-(1-ethylpropyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 106)

NMR (CDCl₃): δ8.86 (1H, d, 8.1 Hz), 7.21 (1H, dd, 8.8, 2.5 Hz), 7.12(1H, d, 2.5 Hz), 6.81 (1H, d, 8.8 Hz), 5.81 (1H, brs), 5.42 (1H, d, 17.5Hz), 4.12 (1H, d, 17.5 Hz), 3.84 (3H, s), 3.78-3.65 (2H, m), 3.34-3.30(2H, m), 3.18 (1H, dd, 14.0, 5.2 Hz), 2.61 (1H, dd, 14.0, 8.5 Hz),1.65-1.43 (4H, m), 0.96-0.89 (6H, m)

MS: 396 (M+H)⁺

Example 1076-(5-chloro-2-methoxybenzyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 107)

NMR (CDCl₃): δ9.42-9.38 (1H, m), 7.35-7.28 (2H, m), 7.22 (1H, dd, 8.7,2.2 Hz), 7.12 (0.5H, d, 2.2 Hz), 7.11 (0.5H, d, 2.2 Hz), 7.07-7.00 (2H,m), 6.81 (0.5H_(r d,) 8.7 Hz), 6.80 (0.5H, d, 8.7 Hz), 5.80-5.73 (1H,m), 5.39 (0.5H, d, 17.6 Hz), 5.37 (0.5H, d, 17.6 Hz), 5.05-4.99 (1H, m),4.12 (0.5H, d, 17.6 Hz), 4.08 (0.5H, d, 17.6 Hz), 3.83 (1.5H, s), 3.82(1.5H, s), 3.72-3.65 (1H, m), 3.35-3.29 (2H, m), 3.17 (1H, dd, 14.0, 5.2Hz), 2.65-2.58 (1H, m), 1.529 (1.5H, d, 7.0 Hz), 1.524 (1.5H, d, 6.9 Hz)

MS: 448 (M+H)⁺

Example 1084-[({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)methyl]benzoicacid (compound 108)

NMR (DMSO-d₆): δ13.15-12.53 (1H, br), 9.41 (1H, t, 5.9 Hz), 7.89 (2H, d,8.2 Hz), 7.68 (1H, d, 3.7 Hz), 7.38 (2H, d, 8.2 Hz), 7.32 (1H, d, 2.7Hz), 7.25 (1H, dd, 8.8, 2.7 Hz), 6.99 (1H, d, 8.8 Hz), 4.78 (1H, d, 17.2Hz), 4.53 (1H, d, 17.2 Hz), 4.46 (1H, d, 5.9 Hz), 4.45 (1H, d, 5.9 Hz),3.91-3.82 (1H, m), 3.78 (3H, s), 3.14 (1H, t, 12.6 Hz), 3.08-2.95 (2H,m), 2.62 (1H, dd, 14.3, 8.6 Hz)

MS: 460 (M+H)⁺

Example 1096-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-(1-phenylbutyl)-1,4-diazepan-1-carboxamide(compound 109)

NMR (CDCl₃): δ9.48 (1H, brd, 7.5 Hz), 7.39-7.20 (6H, m), 7.13 (1H, d,2.6 Hz), 6.81 (0.5H, d, 8.8 Hz), 6.80 (0.5H, d, 8.8 Hz), 5.76 (0.5H,br), 5.71 (0.5H, br), 5.39 (0.5H, d, 17.5 Hz), 5.37 (0.5H, d, 17.5 Hz),4.93-4.84 (1H, m), 4.11 (0.5H, d, 17.5 Hz), 4.06 (0.5H, d, 17.5 Hz),3.84 (1.5H, s), 3.82 (1.5H, s), 3.72-3.62 (1H, m), 3.38-3.28 (2H, m),3.19 (1H, dd, 14.0, 5.2 Hz), 2.66-2.59 (1H, m), 1.91-1.71 (2H, m),1.45-1.23 (2H, m), 0.98-0.87 (3H, m)

MS: 458 (M+H)⁺

Example 1104-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)-4-phenylbutanoicacid (compound 110)

NMR (DMSO-d₆): δ12.29-12.00 (1H, br), 9.39 (0.5H, d, 7.7 Hz), 9.38(0.5H, d, 6.4 Hz), 7.70-7.61 (1H, m), 7.50-7.20 (7H, m), 6.99 (1H, d,8.9 Hz), 4.85-4.77 (1H, m), 4.72 (1H, d, 17.2 Hz), 4.51 (0.5H, d, 17.2Hz), 4.47 (0.5H, d, 17.2 Hz), 3.90-3.80 (1H, m), 3.78 (1.5H, s), 3.77(1.5H, s), 3.22-3.08 (1H, m), 3.04-2.92 (2H, m), 2.70-2.60 (1H, m),2.25-1.90 (4H, m)

MS: 488 (M+H)⁺

Example 1116-(5-chloro-2-methoxybenzyl)-N-(2-methyl-1-phenylpropyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound III)

NMR (CDCl₃): δ9.64 (1H, d, 8.1 Hz), 7.38-7.21 (6H, m), 7.15 (1H, s),6.81 (0.5H, d, 8.7 Hz), 6.80 (0.5H, d, 8.8 Hz), 5.71 (0.5H, br), 5.65(0.5H, br), 5.40 (0.5H, d, 17.6 Hz), 5.37 (0.5H, d, 17.6 Hz), 4.75-4.65(1H, m), 4.12 (0.5H, d, 17.6 Hz), 4.06 (0.5H, d, 17.6 Hz), 3.84 (1.5H,s), 3.83 (1.5H, s), 3.72-3.64 (1H, m), 3.38-3.29 (2H, m), 3.26-3.20 (1H,m), 2.63 (1H, dd, 13.9, 8.4 Hz), 2.12-2.02 (1H, m), 0.90-0.87 (6H, m)

MS: 458 (M+H)⁺

Example 1126-(5-chloro-2-methoxybenzyl)-N-(3-methyl-1-phenylbutyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 112)

NMR (CDCl₃): δ9.45-9.42 (1H, m), 7.39-7.20 (6H, m), 7.13 (1H, d, 2.5Hz), 6.81 (0.5H, d, 8.7 Hz), 6.80 (0.5H, d, 8.7 Hz), 5.74 (0.5H, br),5.69 (0.5H, br), 5.38 (0.5H, d, 17.5 Hz), 5.36 (0.5H, d, 17.5 Hz),5.00-4.89 (1H, m), 4.11 (0.5H, d, 17.5 Hz), 4.05 (0.5H, d, 17.5 Hz),3.84 (1.5H, s), 3.82 (1.5H, s), 3.72-3.62 (1H, m), 3.38-3.27 (2H, m),3.18 (1H, dd, 14.0, 5.1 Hz), 2.60 (1H, dd, 14.0, 8.5 Hz), 1.82-1.73 (1H,m), 1.69-1.49 (2H, m), 0.99-0.85 (6H, m)

MS: 472 (M+H)⁺

Example 113rel-(1R,6R)-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 113)

NMR (DMSO-dd: 812.73 (1H, br), 9.48 (1H, d, J=7.5 Hz), 7.89 (2H, d,J=8.2 Hz), 7.67 (1H, d, J=3.2 Hz), 7.41 (2H, d, J=8.2 Hz), 7.32 (1H, d,J=2.6 Hz), 7.26 (1H, dd, J=8.9, 2.6 Hz), 7.00 (1H, d, J=8.9 Hz),4.79-4.70 (2H, m), 4.48 (1H, d, J=17.1 Hz), 3.91-3.81 (1H, m), 3.78 (3H,s), 3.15 (1H, t, J=12.7 Hz), 3.05-2.93 (2H, m), 2.66 (1H, dd, J=14.3,9.1 Hz), 1.85-1.73 (2H, m), 0.83 (3H, t, J=7.2 Hz)

MS: 488 (M+H)⁺

Example 114rel-(1R,6S)-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 114)

NMR (DMSO-d₆): δ12.71 (1H, br), 9.43 (1H, d, J=7.5 Hz), 7.88 (2H, d,J=8.2 Hz), 7.63 (1H, d, J=3.6 Hz), 7.4 (2H, d, J=8.2 Hz), 7.31 (1H, d,J=2.6 Hz), 7.24 (1H, dd, J=8.9, 2.6 Hz), 6.98 (1H, d, J=8.9 Hz),4.79-4.69 (2H, m), 4.50 (1H, d, J=17.1 Hz), 3.90-3.80 (1H, m), 3.76 (3H,s), 3.11 (1H, t, J=13.0 Hz), 3.00-2.91 (2H, m), 2.63 (1H, dd, J=14.4,9.0 Hz), 1.84-1.69 (2H, m), 0.81 (3H, t, J=7.3 Hz)

MS: 488 (M+H)⁺

Example 115N-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}-2-methylalanine(compound 115)

NMR (CDCl₃): δ9.43 (1H, s), 7.19 (1H, dd, 8.7, 2.5 Hz), 7.11 (1H, d, 2.5Hz), 6.79 (1H, d, 8.7 Hz), 6.65 (1H, s), 5.26 (1H, d, 17.7 Hz), 4.13(1H, d, 17.7 Hz), 3.82 (3H, s), 3.75-3.65 (1H, m), 3.36-3.29 (2H, m),3.17 (1H, dd, 13.9, 5.0 Hz), 2.56 (1H, dd, 13.9, 8.4 Hz), 1.56 (6H, s)

MS: 412 (M+H)⁺

Example 116(3S)-4-anilino-3-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)-4-oxobutanoicacid (compound 116)

NMR (DMSO-d₆): δ12.28-12.20 (1H, m), 10.10 (1H, s), 9.62-9.50 (1H, m),8.20-8.15 (1H, m), 7.53 (2H, d, 8.2 Hz), 7.32-6.89 (6H, m), 4.85-4.69(1H, m), 4.59-4.45 (1H, m), 4.40-4.35 (1H, m), 3.93-3.89 (1H, m), 3.77(3H, s), 3.40-2.60 (6H, m)

MS: 517 (M+H)⁺

Example 1176-(5-chloro-2-methoxybenzyl)-N-[(3S)-2,5-dioxo-1-phenylpyrrolidinyl]-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 117)

NMR (DMSO-d₆): δ9.55-9.51 (1H, m), 7.70 (1H, br), 7.50-7.44 (2H, m),7.41-7.35 (1H, m), 7.327 (0.5H, s), 7.321 (0.5H, s), 7.25-7.19 (3H, m),6.97 (1H, d, 8.8 Hz), 4.98-4.85 (1H, m), 4.77 (0.5H, d, 17.1 Hz), 4.75(0.5H, d, 17.1 Hz), 4.54 (1H, d, 17.1 Hz), 3.96-3.85 (1H, m), 3.77 (3H,s), 3.20-3.00 (3H, m), 2.96 (1H, dd, 14.4, 5.6 Hz), 2.78-2.70 (1H, m),2.59 (1H, dd, 14.4, 6.0 Hz)

MS: 499 (M+H)⁺

Example 118rel-(1R,6R)-3-[1-({[6-(5-fluoro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 118)

NMR (DMSO-d₆): δ12.84 (1H, br), 9.45 (1H, d, J=7.3 Hz), 7.83 (1H, s),7.79 (1H, d, J=7.6 Hz), 7.65 (1H, d, J=3.6 Hz), 7.53 (1H, d, J=7.6 Hz),7.43 (1H, t, J=7.6 Hz), 7.12 (1H, dd, J=9.4, 3.0 Hz), 7.04-6.92 (2H, m),4.75-4.65 (2H, m), 4.46 (1H, d, J=17.1 Hz), 3.90-3.79 (1H, m), 3.74 (3H,s), 3.10 (1H, t, J=12.5 Hz), 3.03-2.91 (2H, m), 2.65 (1H, dd, J=14.5,9.1 Hz), 1.85-1.70 (2H, m), 0.81 (3H, t, J=7.3 Hz)

MS: 472 (M+H)⁺

Example 119(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoicacid (compound 119)

NMR (CDCl₃): δ9.45 (0.5H, d, 6.7 Hz), 9.44 (0.5H, d, 6.5 Hz), 7.24-7.20(1H, m), 7.19-7.10 (0.5H, m), 7.15 (0.5H, d, 2.4 Hz), 7.11 (0.5H, d, 2.5Hz), 6.95 (0.5H, br), 6.817 (0.5H, d, 8.8 Hz), 6.813 (0.5H, d, 8.7 Hz),5.38-5.29 (1H, m), 4.48-4.41 (1H, m), 4.23-4.15 (1H, m), 3.84 (3H, s),3.78-3.65 (1H, m), 3.40-3.33 (2H, m), 3.27-3.15 (1H, m), 2.69-2.58 (1H,m), 2.05-1.80 (2H, m), 1.09-1.00 (3H, m)

MS: 411 (M+H)⁺

Example 1206-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-[(1R)-1-(1H-tetrazol-5-yl)propyl]-1,4-diazepan-1-carboxamide(compound 120)

NMR (DMSO-d₆): δ9.54 (1H, d, 7.4 Hz), 7.66 (1H, br), 7.31 (0.5H, s),7.30 (0.5H, s), 7.24 (0.5H, d, 8.9 Hz), 7.23 (0.5H, d, 8.9 Hz), 6.98(1H, d, 8.9 Hz), 5.09-5.00 (1H, m), 4.78 (0.5H, d, 17.5 Hz), 4.74 (0.5H,d, 17.5 Hz), 4.51 (1H, d, 17.5 Hz), 3.90-3.80 (1H, m), 3.76 (3H, s),3.17-3.05 (1H, m), 3.04-2.90 (2H, m), 2.70-2.55 (1H, m), 1.95-1.71 (2H,m), 0.87-0.69 (3H, m)

MS: 436 (M+H)⁺

Example 121rel-(1R,6S)-3-[1-({[6-(5-fluoro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 121)

NMR (DMSO-d₆): δ9.42 (1H, d, J=7.5 Hz), 7.81 (1H, s), 7.78 (1H, d, J=7.5Hz), 7.61 (1H, d, J=3.3 Hz), 7.44 (1H, d, J=7.5 Hz), 7.38 (1H, t, J=7.5Hz), 7.12 (1H, dd, J=9.4, 3.1 Hz), 7.05-6.92 (2H, m), 4.77-4.68 (2H, m),4.50 (1H, d, J=17 Hz), 3.91-3.80 (1H, m), 3.75 (3H, s), 3.10 (1H, t,J=12.9 Hz), 3.03-2.92 (2H, m), 2.63 (1H, dd, J=14.5, 9.0 Hz), 1.84-1.69(2H, m), 0.79 (3H, t, J=7.2 Hz)

MS: 472 (M+H)⁺

Example 122N-[1-(4-aminophenyl)propyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamidehydrochloride (compound 122) (diastereomer of Compound 123)

NMR (DMSO-d₆): δ9.40 (1H, d, J=7.5 Hz), 7.65 (1H, brd, J=3.6 Hz), 7.35(2H, d, J=8.1 Hz), 7.33 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.7, 2.6 Hz),7.19 (2H, d, J=8.1 Hz), 7.01 (1H, d, J=8.7 Hz), 4.75 (1H, d, J=17.2 Hz),4.68 (1H, dd, J=14.4, 7.3 Hz), 4.53 (1H, d, J=17.2 Hz), 3.93-3.83 (1H,m), 3.79 (3H, s), 3.17-2.95 (3H, m), 2.70-2.61 (1H, m), 1.88-1.70 (2H,m), 0.83 (3H, t, J=7.3 Hz)

MS: 459 (M+H)⁺

Example 123N-[1-(4-aminophenyl)propyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamidehydrochloride (compound 123) (diastereomer of Compound 122)

NMR (DMSO-d₆): δ9.39 (1H, d, J=7.5 Hz), 7.66 (1H, brd, J=3.6 Hz),7.34-7.28 (3H, m), 7.24 (1H, dd, J=8.8, 2.6 Hz), 7.14 (2H, d, J=8.0 Hz),6.98 (1H, d, J=8.8 Hz), 4.70 (1H, d, J=17.2 Hz), 4.64 (1H, dd, J=14.4,7.2 Hz), 4.46 (1H, d, J=17.2 Hz), 3.89-3.79 (1H, m), 3.76 (3H, s),3.18-2.91 (3H, m), 2.69-2.60 (1H, m), 1.83-1.69 (2H, m), 0.80 (3H, t,J=7.3 Hz)

MS: 459 (M+H)⁺

Example 1243-[(1S)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 124)

NMR (DMSO-d₆): δ13.01 (1H, br), 9.48 (1H, d, J=7.3 Hz), 7.86 (1H, s),7.82 (1H, d, J=7.7 Hz), 7.67 (1H, d, J=3.5 Hz), 7.55 (1H, d, J=7.7 Hz),7.46 (1H, t, J=7.7 Hz), 7.33 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.8, 2.6Hz), 7.00 (1H, d, J=8.8 Hz), 4.79-4.69 (2H, m), 4.49 (1H, d, J=17.2 Hz),3.91-3.81 (1H, m), 3.79 (3H, s), 3.16 (1H, t, J=12.6 Hz), 3.05-2.96 (2H,m), 2.67 (1H, dd, J=14.3, 9.3 Hz), 1.89-1.74 (2H, m), 0.84 (3H, t, J=7.3Hz)

MS: 488 (M+H)⁺

Example 1253-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 125)

NMR (DMSO-d₆): δ12.92 (1H, br), 9.45 (1H, d, J=7.4 Hz), 7.86 (1H, s),7.83 (1H, d, J=7.6 Hz), 7.64 (1H, d, J=3.2 Hz), 7.56 (1H, d, J=7.6 Hz),7.47 (1H, t, J=7.6 Hz), 7.33 (1H, d, J=2.4 Hz), 7.27 (1H, dd, J=8.9, 2.4Hz), 7.01 (1H, d, J=8.9 Hz), 4.80-4.72 (2H, m), 4.52 (1H, d, J=17.2 Hz),3.92-3.82 (1H, m), 3.79 (3H, s), 3.12 (1H, t, J=12.7 Hz), 3.03-2.94 (2H,m), 2.65 (1H, dd, J=14.2, 9.0 Hz), 1.87-1.71 (2H, m), 0.84 (3H, t, J=7.2Hz)

MS: 488 (M+H)⁺

Example 1263-[(1S)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 126)

NMR (DMSO-d₆): δ12.92 (1H, br), 9.45 (1H, d, J=7.4 Hz), 7.86 (1H, s),7.83 (1H, d, J=7.6 Hz), 7.64 (1H, d, J=3.2 Hz), 7.56 (1H, d, J=7.6 Hz),7.47 (1H, t, J=7.6 Hz), 7.33 (1H, d, J=2.4 Hz), 7.27 (1H, dd, J=8.9, 2.4Hz), 7.01 (1H, d, J=8.9 Hz), 4.80-4.72 (2H, m), 4.52 (1H, d, J=17.2 Hz),3.92-3.82 (1H, m), 3.79 (3H, s), 3.12 (1H, t, J=12.7 Hz), 3.03-2.94 (2H,m), 2.65 (1H, dd, J=14.2, 9.0 Hz), 1.87-1.71 (2H, m), 0.84 (3H, t, J=7.2Hz)

MS: 488 (M+H)⁺

Example 1276-(5-chloro-2-methoxybenzyl)-N-{1-[3-(methylsulfonyl)phenyl]propyl}-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 127)

NMR (CDCl₃): δ9.56 (1H, brd, J=4.8 Hz), 7.88-7.79 (2H, m), 7.60-7.47(2H, m), 7.22 (1H, dd, J=8.7, 2.5 Hz), 7.15 (0.5H, d, J=2.5 Hz), 7.14(0.5H, d, J=2.5 Hz), 6.83 (0.5H, d, J=8.7 Hz), 6.82 (0.5H, d, J=8.7 Hz),5.70-5.60 (1H, br), 5.35 (0.5H, d, J=17.0 Hz), 5.30 (0.5H, d, J=17.0Hz), 4.86 (1H, dd, J=14.3, 7.3 Hz), 4.13 (0.5H, d, J=17.0 Hz), 4.11(0.5H, d, J=17.0 Hz), 3.85 (1.5H, s), 3.84 (1.5H, s), 3.77-3.66 (1H, m),3.38-3.31 (2H, m), 3.25-3.18 (1H, m), 3.07 (1.5H, s), 3.06 (1.5H, s),2.70-2.60 (1H, m), 1.94-1.82 (2H, m), 1.00-0.90 (3H, m)

MS: 522 (M+H)⁺

Example 1286-(5-chloro-2-methoxybenzyl)-N-{1-[4-(methylsulfonyl)phenyl]propyl}-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 128) (diastereomer of Compound 129)

NMR (CDCl₃): δ9.57 (1H, d, J=7.1 Hz), 7.91 (2H, d, J=8.2 Hz), 7.48 (2H,d, J=8.2 Hz), 7.23 (1H, dd, J=8.7, 2.7 Hz), 7.15 (1H, d, J=2.7 Hz), 6.82(1H, d, J=8.7 Hz), 5.75-5.70 (1H, br), 5.32 (1H, d, J=17.3 Hz), 4.85(1H, dd, J=14.2, 7.1 Hz), 4.09 (1H, d, J=17.3 Hz), 3.83 (3H, s),3.76-3.67 (1H, m), 3.38-3.30 (2H, m), 3.20 (1H, dd, J=14.0, 5.5 Hz),3.04 (3H, s), 2.65 (1H, dd, J=14.0, 8.0 Hz), 1.92-1.79 (2H, m), 0.96(3H, t, J=7.3 Hz)

MS: 522 (M+H)⁺

Example 1296-(5-chloro-2-methoxybenzyl)-N-{1-[4-(methylsulfonyl)phenyl]propyl}-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 129) (diastereomer of Compound 128)

NMR (CDCl₃): δ9.57 (1H, d, J=7.0 Hz), 7.92 (2H, d, J=8.3 Hz), 7.49 (2H,d, J=8.3 Hz), 7.23 (1H, dd, J=8.7, 2.6 Hz), 7.15 (1H, d, J=2.6 Hz), 6.82(1H, d, J=8.7 Hz), 5.62-5.57 (1H, br), 5.34 (1H, d, J=17.7 Hz), 4.85(1H, dd, J=14.2, 7.3 Hz), 4.14 (1H, d, J=17.7 Hz), 3.85 (3H, s),3.76-3.64 (1H, m), 3.35-3.28 (2H, m), 3.20 (1H, dd, J=14.0, 5.5 Hz),3.06 (3H, s), 2.64 (1H, dd, J=14.0, 8.4 Hz), 1.91-1.78 (2H, m), 0.95(3H, t, J=7.4 Hz)

MS: 522 (M+H)⁺

Example 1304-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-hydroxybenzoicacid (compound 130) (diastereomer of Compound 149)

NMR (DMSO-d₆): δ9.44 (1H, d, J=7.4 Hz), 7.74 (1H, d, J=8.6 Hz), 7.67(1H, d, J=3.4 Hz), 7.34 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.9, 2.6 Hz),7.01 (1H, d, J=8.9 Hz), 6.87-6.84 (2H, m), 4.73 (1H, d, J=17.2 Hz), 4.68(1H, q, J=7.4 Hz), 4.50 (1H, d, J=17.2 Hz), 3.92-3.81 (1H, m), 3.79 (3H,s), 3.16 (1H, t, J=12.5 Hz), 3.06-2.94 (2H, m), 2.67 (1H, dd, J=14.3,9.3 Hz), 1.82-1.72 (2H, m), 0.84 (3H, t, J=7.1 Hz)

MS: 504 (M+H)⁺

Example 131rel-(1R,6R)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-thiophencarboxylic acid (compound 131)

NMR (DMSO-d₆): δ9.37 (1H, d, J=8.0 Hz), 7.68-7.63 (1H, br), 7.32 (1H, d,J=2.7 Hz), 7.25 (1H, dd, J=8.8, 2.7 Hz), 7.03-6.94 (1H, br), 6.99 (1H,d, J=8.8 Hz), 6.80-6.73 (1H, br), 4.88 (1H, dd, J=14.3, 7.1 Hz), 4.79(1H, d, J=17.4 Hz), 4.51 (1H, d, J=17.4 Hz), 3.90-3.79 (1H, m), 3.77(3H, s) 3.18-3.12 (1H, m), 3.03-2.90 (2H, m), 2.67-2.60 (1H, m),1.86-1.75 (2H, m), 0.86 (3H, t, J=7.3 Hz)

MS: 494 (M+H)⁺

Example 132rel-(1R,6S)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-thiophencarboxylic acid (compound 132)

NMR (DMSO-d₆): δ9.36 (1H, d, J=8.0 Hz), 7.66-7.62 (1H, br), 7.31 (1H, d,J=2.7 Hz), 7.25 (1H, dd, J=8.7, 2.7 Hz), 7.03-6.93 (1H, br), 6.99 (1H,d, J=8.7 Hz), 6.78-6.72 (1H, br), 4.88 (1H, dd, J=14.3, 7.1 Hz), 4.78(1H, d, J=17.7 Hz), 4.51 (1H, d, J=17.7 Hz), 3.90-3.79 (1H, m), 3.78(3H, s) 3.18-3.07 (1H, m), 3.01-2.90 (2H, m), 2.63-2.55 (1H, m),1.86-1.75 (2H, m), 0.85 (3H, t, J=7.3 Hz)

MS: 494 (M+H)⁺

Example 133rel-(1R,6R)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-furancarboxylic acid (compound 133)

NMR (DMSO-d₆): δ13.05-12.95 (1H, br), 9.36 (1H, d, J=7.9 Hz), 7.70-7.63(1H, br), 7.31 (1H, d, J=2.7 Hz), 7.25 (1H, dd, J=8.7, 2.7 Hz),7.11-7.02 (1H, br), 6.99 (1H, d, J=8.7 Hz), 6.48-6.42 (1H, br), 4.86(1H, dd, J=14.7, 7.3 Hz), 4.76 (1H, d, J=17.4 Hz), 4.51 (1H, d, J=17.4Hz), 3.90-3.79 (1H, m), 3.78 (3H, s) 3.18-3.07 (1H, m), 3.04-2.90 (2H,m), 2.63-2.55 (1H, m), 1.90-1.78 (2H, m), 0.85 (3H, t, J=7.3 Hz)

MS: 478 (M+H)⁺

Example 134rel-(1R,6S)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-furancarboxylic acid (compound 134)

NMR (DMSO-d₆): δ9.35 (1H, d, J=8.2 Hz), 7.66 (1H, brd, J=3.6 Hz), 7.31(1H, d, J=2.6 Hz), 7.26 (1H, dd, J=8.7, 2.6 Hz), 6.99 (1H, d, J=8.7 Hz),6.98-6.87 (1H, br), 6.43-6.36 (1H, br), 4.84 (1H, dd, J=14.8, 7.3 Hz),4.78 (1H, d, J=17.3 Hz), 4.53 (1H, d, J=17.3 Hz), 3.90-3.79 (1H, m),3.78 (3H, s) 3.15 (1H, t, J=12.9 Hz), 3.01-2.90 (2H, m), 2.64-2.57 (1H,m), 1.88-1.72 (2H, m), 0.84 (3H, t, J=7.3 Hz)

MS: 478 (M+H)⁺

Example 135N-{1-[3-(aminosulfonyl)phenyl]propyl}-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 135)

NMR (DMSO-d₆): δ9.47 (0.5H, d, J=7.4 Hz), 9.45 (0.5H, d, J=7.5 Hz), 7.75(1H, s), 7.73-7.60 (2H, m), 7.56-7.50 (2H, m), 7.35-7.30 (3H, m), 7.26(1H, dd, J=8.7, 2.7 Hz), 7.00 (1H, d, J=8.7 Hz), 4.79-4.68 (2H, m), 4.52(0.5H, d, J=17.0 Hz), 4.49 (0.5H, d, J=17.0 Hz), 3.92-3.80 (1H, m),3.779 (1.5H, s), 3.783 (1.5H, s), 3.20-2.92 (3H, m), 2.70-2.60 (1H, m),1.94-1.72 (2H, m), 0.85 (3H, t, J=7.1 Hz)

MS: 523 (M+H)⁺

Example 136N-{1-[4-(aminosulfonyl)phenyl]propyl}-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 136)

NMR (DMSO-d₆): δ9.46 (0.5H, d, J=7.3 Hz), 9.43 (0.5H, d, J=7.4 Hz), 7.78(1H, d, J=8.3 Hz), 7.77 (1H, d, J=8.3 Hz), 7.65 (1H, brd, J=8.6 Hz),7.49 (1H, d, J=8.3 Hz), 7.48 (1H, d, J=8.3 Hz), 7.33 (1H, d, J=2.7 Hz),7.30-7.22 (3H, m), 7.00 (1H, d, J=8.7 Hz), 4.77-4.69 (2H, m), 4.52(0.5H, d, J=16.3 Hz), 4.48 (0.5H, d, J=16.4 Hz), 3.93-3.80 (1H, m), 3.78(3H, s), 3.20-2.92 (3H, m), 2.70-2.60 (1H, m), 1.88-1.70 (2H, m), 0.84(3H, t, J=7.3 Hz)

MS: 523 (M+H)⁺

Example 1376-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-pyridinecarboxylic acid (compound 137)

NMR (DMSO-d₆): δ9.53-9.45 (1H, br), 8.05-7.60 (3H, br), 7.40-7.20 (1H,br), 7.32 (1H, d, J=2.5 Hz), 7.26 (1H, dd, J=8.7, 2.5 Hz), 7.00 (1H, d,J=8.7 Hz), 4.93-4.70 (2H, m), 4.52 (0.5H, d, J=13.0 Hz), 4.48 (0.5H, d,J=17.3 Hz), 3.90-3.80 (1H, m), 3.78 (3H, s), 3.22-2.93 (3H, m),2.72-2.60 (1H, m), 1.95-1.70 (2H, m), 0.90-0.75 (3H, br)

MS: 489 (M+H)⁺

Example 1385-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]nicotinicacid (compound 138)

NMR (DMSO-d₆): δ9.48 (0.5H, d, J=7.2 Hz), 9.44 (0.5H, d, J=7.3 Hz), 8.91(1H, brs), 8.50 (1H, brs), 8.08 (1H, brs), 7.69-7.60 (1H, br), 7.32 (1H,d, J=2.3 Hz), 7.25 (1H, dd, J=8.7, 2.3 Hz), 6.99 (1H, d, J=8.7 Hz),4.79-4.64 (2H, m), 4.52 (0.5H, d, J=18.2 Hz), 4.47 (0.5H, d, J=17.4 Hz),3.90-3.78 (1H, m), 3.77 (1.5H, s), 3.78 (1.5H, s), 3.20-3.08 (1H, m),3.02-2.92 (2H, m), 2.70-2.60 (1H, m), 1.92-1.72 (2H, m), 0.84 (3H, t,J=7.3 Hz)

MS: 489 (M+H)⁺

Example 1392-amino-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 139)

NMR (DMSO-d₆): δ9.30 (0.5H, d, 7.6 Hz), 9.27 (0.5H, d, 7.7 Hz),9.10-7.90 (2H, br), 7.64 (0.5H, d, 3.5 Hz), 7.62 (0.5H, d, 3.8 Hz), 7.56(0.5H, s), 7.56 (0.5H, s), 7.29 (0.5H, s), 7.29 (0.5H, s), 7.26-7.22(1H, m), 7.17-7.14 (1H, m), 6.97 (0.5H, d, 8.8 Hz), 6.97 (0.5H, d, 8.9Hz), 6.69 (0.5H, d, 8.5 Hz), 6.68 (0.5H, d, 8.5 Hz), 4.74 (0.5H, d, 17.2Hz), 4.72 (0.5H, d, 17.1 Hz), 4.51-4.42 (2H, m), 3.86-3.78 (1H, m), 3.75(1.5H, s), 3.75 (1.5H, s), 3.10 (0.5H, dd, 17.7, 13.0 Hz), 3.07 (0.5H,dd, 17.7, 12.4 Hz), 2.99-2.86 (2H, m), 2.65-2.56 (1H, m), 1.80-1.62 (2H,m), 0.79-0.74 (3H, m)

MS: 503 (M+H)⁺

Example 140rel-(1R,6R)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-fluorobenzoicacid (compound 140)

NMR (DMSO-d₆): δ13.34-13.01 (1H, br), 9.40 (1H, d, 7.2 Hz), 7.74 (1H,dd, 7.0, 2.3 Hz), 7.65 (1H, d, 3.7 Hz), 7.57-7.53 (1H, m), 7.30 (1H, d,2.7 Hz), 7.27-7.21 (2H, m), 6.97 (1H, d, 8.8 Hz), 4.71-4.65 (2H, m),4.45 (1H, d, 17.0 Hz), 3.86-3.81 (1H, m), 3.75 (3H, s), 3.13 (1H, t,12.9 Hz), 2.99-2.92 (2H, m), 2.66-2.60 (1H, m), 1.88-1.69 (2H, m), 0.80(3H, t, 7.2 Hz)

MS: 506 (M+H)⁺

Example 141rel-(1R,6S)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-fluorobenzoicacid (compound 141)

NMR (DMSO-d₆): δ13.40-13.10 (1H, br), 9.37 (1H, d, 7.3 Hz), 7.74 (1H,dd, 6.9, 2.1 Hz), 7.63 (1H, d, 3.6 Hz), 7.56-7.53 (1H, m), 7.30 (1H, d,2.6 Hz), 7.28-7.22 (2H, m), 6.97 (1H, d, 8.8 Hz), 4.75-4.65 (2H, m),4.49 (1H, d, 17.1 Hz), 3.87-3.81 (1H, m), 3.76 (3H, s), 3.09 (1H, t,13.0 Hz), 2.98-2.92 (2H, m), 2.66-2.60 (1H, m), 1.88-1.68 (2H, m), 0.80(3H, t, 7.2 Hz)

MS: 506 (M+H)⁺

Example 1423-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-4-methoxybenzoicacid (compound 142) (diastereomer of Compound 143)

NMR (DMSO-d₆): δ12.90-12.30 (1H, br), 9.68 (1H, d, 8.4 Hz), 7.82 (1H,dd, 8.5, 2.0 Hz), 7.71 (1H, d, 2.0 Hz), 7.66 (1H, d, 3.5 Hz), 7.31 (1H,d, 2.6 Hz), 7.23 (1H, dd, 8.7, 2.6 Hz), 7.05 (1H, d, 8.5 Hz), 6.96 (1H,d, 8.7 Hz), 4.95-4.89 (1H, m), 4.73 (1H, d, 17.2 Hz), 4.43 (1H, d, 17.2Hz), 3.90-3.80 (1H, m), 3.85 (3H, s), 3.75 (3H, s), 3.13 (1H, t, 12.8Hz), 3.02-2.92 (2H, m), 2.68-2.61 (1H, m), 1.78-1.65 (2H, m), 0.78 (3H,t, 7.3 Hz)

MS: 518 (M+H)⁺

Example 1433-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-4-methoxybenzoicacid (compound 143) (diastereomer of Compound 142)

NMR (DMSO-d₆): δ12.80-12.45 (1H, br), 9.64 (1H, d, 8.5 Hz), 7.83 (1H,dd, 8.6, 2.0 Hz), 7.71 (1H, d, 2.0 Hz), 7.62 (1H, d, 3.4 Hz), 7.31 (1H,d, 2.6 Hz), 7.24 (1H, dd, 8.7, 2.6 Hz), 7.08 (1H, d, 8.6 Hz), 6.97 (1H,d, 8.7 Hz), 4.97-4.90 (1H, m), 4.74 (1H, d, 17.1 Hz), 4.49 (1H, d, 17.1Hz), 3.92-3.80 (1H, m), 3.87 (3H, s), 3.76 (3H, s), 3.03 (1H, t, 12.4Hz), 2.98-2.93 (2H, m), 2.66-2.59 (1H, m), 1.76-1.68 (2H, m), 0.77 (3H,t, 7.3 Hz)

MS: 518 (M+H)⁺

Example 144rel-(1R,6R)-2-amino-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 144)

NMR (DMSO-d₆): δ9.39 (1H, d, 7.6 Hz), 7.65 (1H, d, 3.7 Hz), 7.61 (1H, d,8.3 Hz), 7.30 (1H, d, 2.6 Hz), 7.24 (1H, dd, 8.7, 2.6 Hz), 6.97 (1H, d,8.7 Hz), 6.60 (1H, s), 6.40 (1H, d, 8.3 Hz), 5.72 (2H, s), 4.73 (1H, d,17.1 Hz), 4.54-4.45 (2H, m), 3.87-3.80 (1H, m), 3.76 (3H, s), 3.12 (1H,t, 12.6 Hz), 3.00-2.91 (2H, m), 2.67-2.60 (1H, m), 1.77-1.49 (2H, m),0.80 (3H, t, 7.2 Hz)

MS: 503 (M+H)⁺

Example 145rel-(1R,6S)-2-amino-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 145)

NMR (DMSO-d₆): δ9.37 (1H, d, 7.7 Hz), 7.63 (1H, brs), 7.62 (1H, d, 7.6Hz), 7.30 (1H, d, 2.6 Hz), 7.24 (1H, dd, 8.7, 2.6 Hz), 6.98 (1H, d, 8.7Hz), 6.57 (1H, s), 6.39 (1H, d, 7.6 Hz), 5.72 (2H, s), 4.76 (1H, d, 17.0Hz), 4.55-4.46 (2H, m), 3.90-3.81 (1H, m), 3.76 (3H, s), 3.10 (1H, t,12.7 Hz), 3.00-2.91 (2H, m), 2.65-2.55 (1H, m), 1.74-1.65 (2H, m), 0.79(3H, t, 7.2 Hz)

MS: 503 (M+H)⁺

Example 146rel-(1R,6R)-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-fluorobenzoicacid (compound 146)

NMR (DMSO-d₆): δ13.38-12.86 (1H, br), 9.40 (1H, d, 7.4 Hz), 7.73 (1H, t,7.8 Hz), 7.65 (1H, d, 3.4 Hz), 7.31 (1H, d, 2.6 Hz), 7.24 (1H, dd, 8.7,2.6 Hz), 7.20-7.11 (2H, m), 6.98 (1H, d, 8.7 Hz), 4.73-4.66 (2H, m),4.47 (1H, d, 17.2 Hz), 4.01-3.80 (1H, m), 3.76 (3H, s), 3.13 (1H, t,12.8 Hz), 3.05-2.90 (2H, m), 2.64 (1H, dd, 11.3, 9.4 Hz), 1.81-1.72 (2H,m), 0.82 (3H, t, 7.2 Hz)

MS: 506 (M+H)⁺

Example 147rel-(1R,6S)-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-fluorobenzoicacid (compound 147)

NMR (DMSO-d₆): δ13.40-12.80 (1H, br), 9.37 (1H, d, 7.5 Hz), 7.79-7.70(1H, br), 7.64 (1H, d, 3.8 Hz), 7.31 (1H, d, 2.6 Hz), 7.27-7.15 (3H, m),6.98 (1H, d, 8.8 Hz), 4.75-4.67 (2H, m), 4.50 (1H, d, 17.1), 4.00-3.80(1H, m), 3.76 (3H, s), 3.13 (1H, t, 12.7 Hz), 3.00-2.92 (2H, m),2.67-2.57 (1H, m), 1.82-1.67 (2H, m), 0.81 (3H, t, 7.2 Hz)

MS: 506 (M+H)⁺

Example 1485-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-furancarboxylic acid (compound 148)

NMR (DMSO-d₆): δ9.35 (1H, d, J=7.9 Hz), 7.69-7.60 (1H, br), 7.30 (1H,s), 7.24 (1H, d, J=8.7 Hz), 7.11 (1H, d, J=3.4 Hz), 6.97 (1H, d, J=8.7Hz), 6.46 (1H, d, J=3.4 Hz), 4.85 (1H, dd, J=14.4, 7.1 Hz), 4.74 (1H, d,J=17.3 Hz), 4.50 (1H, d, J=17.3 Hz), 3.89-3.78 (1H, m), 3.76 (3H, s),3.17-2.88 (3H, m), 2.65-2.57 (1H, m), 1.89-1.77 (2H, m), 0.84 (3H, t,J=7.3 Hz)

MS: 478 (M+H)⁺

Example 1494-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-hydroxybenzoicacid (compound 149) (diastereomer of Compound 130)

NMR (DMSO-d₆): δ9.41 (1H, d, J=7.5 Hz), 7.75 (1H, d, J=8.5 Hz), 7.66(1H, d, J=3.8 Hz), 7.34 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.7, 2.6 Hz),7.01 (1H, d, J=8.5 Hz), 6.90-6.85 (2H, m), 4.74 (1H, d, J=17.1 Hz),4.72-4.66 (1H, m), 4.53 (1H, d, J=17.1 Hz), 3.93-3.84 (1H, m), 3.79 (3H,s), 3.14 (1H, t, J=13.1 Hz), 3.05-2.95 (2H, m), 2.66 (1H, dd, J=14.2,9.2 Hz), 1.83-1.72 (2H, m), 0.84 (3H, t, J=7.3 Hz)

MS: 504 (M+H)⁺

Example 1502-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 150)

(Step 1) To the compound S141B (1.5 g) in N,N-dimethylformamide (15 ml)solution, 4-dimethylaminopyridine (0.3 g), the compound S102 (0.97 g),and triethylamine (0.68 ml) were added under ice cooling and the mixturewas stirred under ice cooling for 16 hours. Saturated ammonium chlorideaqueous solution was added to the reaction solution and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate-1/3) to obtain tert-butyl2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(1.47 g).

NMR (CDCl₃): δ9.42 (1H, d, J=7.9 Hz), 7.77 (1H, d, J=8.7 Hz), 7.18 (1H,dd, J=8.7, 2.6 Hz), 6.93 (1H, d, J=2.6 Hz), 6.75 (1H, d, J=8.8 Hz),6.55-6.50 (2H, m), 6.01 (2H, s), 5.7 (2H, br), 5.31 (1H, d, J=17.5 Hz),4.82 (1H, d, J=13.8 Hz), 4.7 (1H, q, J=7.9 Hz), 4.29-4.20 (2H, m), 3.81(3H, s), 3.77 (3H, s), 3.61-3.50 (7H, m), 3.1 (1H, dd, J=13.7, 4.7 Hz),3.01-2.95 (2H, m), 2.4 (1H, dd, J=13.7, 9.2 Hz), 1.88-1.71 (2H, m), 1.58(9H, s), 0.88 (3H, t, J=7.4 Hz)

(Step 2) To tert-butyl2-amino-4-[(1R)-1-({[(65)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(1.47 g), 1M hydrogen chloride/acetic acid solution (15 ml) was addedand the mixture was stirred at room temperature for 20 hours. Thereaction solution was concentrated, then the residue was purified bysilica gel column chromatography (chloroform/ethylacetate/methanol/acetic acid=8/8/1/0.1) to obtain the title compound(0.28 g).

NMR (DMSO-d₆): δ9.41 (1H, d, 7.7 Hz), 7.67 (1H, br), 7.66 (1H, d, 8.2Hz), 7.33 (1H, d, 2.7 Hz), 7.27 (1H, dd, 8.8, 2.7 Hz), 7.01 (1H, d, 8.8Hz), 6.64 (1H, d, 1.5 Hz), 6.45 (1H, dd, 8.2, 1.5 Hz), 4.79 (1H, d, 17.2Hz), 4.59-4.49 (1H, m), 4.53 (1H, d, 17.2 Hz), 3.92-3.84 (1H, m), 3.79(3H, s), 3.14 (1H, t, 12.8 Hz), 3.00 (1H, dd, 17.0, 12.8 Hz), 2.98 (1H,dd, 14.4, 4.6 Hz), 2.65 (1H, dd, 14.4, 9.2 Hz), 1.79-1.67 (2H, m), 0.83(3H, t, 7.2 Hz)

MS: 503 (M+H)⁺

Example 1515-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]nicotinicacid (compound 151)

The compound S141C was used instead of the starting material compound ofReference Example 142A, that is, the compound S141A, and the compoundS103 was used instead of the starting material compound of ReferenceExample 142A, that is, the compound S83, for the similar procedure as inReference Example 142A and Example 91 to obtain the title compound.

NMR (DMSO-d₆): δ9.48 (1H, d, J=7.1 Hz), 8.93 (1H, d, J=1.8 Hz), 8.71(1H, brs), 8.17 (1H, s), 7.67 (1H, brd, J=3.8 Hz), 7.34 (1H, d, J=2.7Hz), 7.27 (1H, dd, J=8.7, 2.7 Hz), 7.01 (1H, d, J=8.7 Hz), 4.79 (1H, dd,J=14.2, 7.0 Hz), 4.69 (1H, d, J=17.1 Hz), 4.49 (1H, d, J=17.1 Hz),3.92-3.80 (1H, m), 3.79 (3H, s), 3.17 (1H, t, J=12.9 Hz), 3.07-2.97 (2H,m), 2.78-2.65 (1H, m), 1.95-1.78 (2H, m), 0.87 (3H, t, J=7.3 Hz)

MS: 489 (M+H)⁺

Melting point: 138-140° C.

Example 152(6R)—N-[1-(3-hydroxy-5-isoxazole)propyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 152) (diastereomer of Compound 153)

Instead of the starting material compound of Example 151, that is, thecompound S103, the compound S94 was used for the similar procedure as inExample 151 to obtain the title compound.

NMR (DMSO-d₆): δ11.45-11.05 (1H, br), 9.37 (1H, d, 7.9 Hz), 7.69 (1H,brd, 3.9 Hz), 7.33 (1H, d, 2.7 Hz), 7.27 (1H, dd, 8.8, 2.7 Hz), 7.00(1H, d, 8.8 Hz), 5.90 (1H, s), 4.83 (1H, dd, 14.4, 7.9 Hz), 4.75 (1H, d,17.2), 4.53 (1H, d, 17.2 Hz), 3.92-3.82 (1H, m), 3.79 (3H, s), 3.15 (1H,t, 13.2 Hz), 3.04-2.94 (2H, m), 2.68-2.61 (1H, m), 1.91-1.77 (2H, m),0.87 (3H, t, 7.3 Hz)

MS: 451 (M+H)⁺

Example 153(6S)—N-[1-(3-hydroxy-5-isoxazole)propyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 153) (diastereomer of Compound 152)

Instead of the starting material compound of Example 151, that is, thecompound S103, the compound S94 was used for the similar procedure as inExample 151 to obtain the title compound.

NMR (DMSO-d₆): δ11.50-11.05 (1H, br), 9.37 (1H, d, 8.0 Hz), 7.69 (1H,brd, 3.7 Hz), 7.33 (1H, d, 2.7 Hz), 7.27 (1H, dd, 8.8, 2.7 Hz), 7.01(1H, d, 8.8 Hz), 5.93 (1H, s), 4.84 (1H, dd, 14.3, 8.0 Hz), 4.76 (1H, d,17.1 Hz), 4.55 (1H, d, 17.1 Hz), 3.91-3.84 (1H, m), 3.79 (3H, s), 3.16(1H, t, 13.0 Hz), 3.03-2.94 (2H, m), 2.65 (1H, dd, 14.3, 9.0 Hz),1.89-1.76 (2H, m), 0.87 (3H, t, 7.3 Hz)

MS: 451 (M+H)⁺

Example 1545-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-3-furancarboxylic acid (compound 154)

Instead of starting material compound of Example 151, that is, thecompound S103, the compound S104 was used for the similar procedure asin Example 151 to obtain the title compound.

NMR (DMSO-d₆): δ12.71-12.59 (1H, br), 9.36 (1H, d, J=8.1 Hz), 8.20 (1H,brs), 7.69 (1H, brd, J=3.9 Hz), 7.33 (1H, d, J=2.6 Hz), 7.27 (1H, dd,J=8.8, 2.6 Hz), 7.01 (1H, d, J=8.8 Hz), 6.54 (1H, s), 4.85 (1H, dd,J=14.7, 7.1 Hz), 4.78 (1H, d, J=17.1 Hz), 4.52 (1H, d, J=17.1 Hz),3.91-3.81 (1H, m), 3.79 (3H, s) 3.15 (1H, t, J=12.5 Hz), 3.07-2.92 (2H,m), 2.68-2.57 (1H, m), 1.89-1.75 (2H, m), 0.86 (3H, t, J=7.3 Hz)

MS: 478 (M+H)⁺

Example 1555-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-3-thiophencarboxylicacid (compound 155)

Instead of the starting material compound of Example 151, that is, thecompound S103, the compound S108 was used for the similar procedure asin Example 151 to obtain the title compound.

NMR (DMSO-d₆): δ12.80-12.65 (1H, br), 9.42 (1H, d, J=7.8 Hz), 8.09 (1H,brs), 7.69 (1H, brd, J=3.5 Hz), 7.33 (1H, d, J=2.6 Hz), 7.30-7.24 (2H,m), 7.01 (1H, d, J=8.8 Hz), 4.97 (1H, dd, J=14.3, 7.1 Hz), 4.77 (1H, d,J=17.1 Hz), 4.53 (1H, d, J=17.1 Hz), 3.93-3.84 (1H, m), 3.79 (3H, s)3.15 (1H, t, J=12.5 Hz), 3.07-2.94 (2H, m), 2.68-2.58 (1H, m), 1.94-1.85(2H, m), 0.89 (3H, t, J=7.3 Hz)

MS: 494 (M+H)⁺

Example 1562-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]isonicotinicacid (compound 156)

Instead of the starting material compound of Example 151, that is, thecompound S103, the compound S105 was used for the similar procedure asin Example 151 to obtain the title compound.

NMR (DMSO-d₆): δ9.75 (1H, d, J=7.6 Hz), 8.75 (1H, d, J=4.9 Hz), 7.81(1H, brs), 7.75-7.68 (2H, m), 7.34 (1H, d, J=2.7 Hz), 7.27 (1H, dd,J=8.8, 2.7 Hz), 7.01 (1H, d, J=8.8 Hz), 4.96 (1H, dd, J=14.1, 7.0 Hz),4.77 (1H, d, J=17.2 Hz), 4.50 (1H, d, J=17.2 Hz), 3.94-3.80 (1H, m),3.79 (3H, s), 3.17 (1H, t, J=13.0 Hz), 3.07-2.97 (2H, m), 2.72-2.64 (1H,m), 1.92-1.80 (2H, m), 0.80 (3H, t, J=7.4 Hz)

MS: 489 (M+H)⁺

Example 1576-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]nicotinicacid (compound 157)

Instead of the starting material compound of Example 151, that is, thecompound S103, the compound S106 was used for the similar procedure asin Example 151 to obtain the title compound.

NMR (DMSO-d₆): δ9.75 (1H, d, J=7.5 Hz), 9.04 (1H, d, J=2.1 Hz), 8.25(1H, dd, J=8.1, 2.1 Hz), 7.70 (1H, brd, J=3.9 Hz), 7.53 (1H, d, J=8.1Hz), 7.34 (1H, d, J=2.7 Hz), 7.27 (1H, dd, J=8.7, 2.7 Hz), 7.01 (1H, d,J=8.7 Hz), 4.94 (1H, dd, J=14.1, 7.0 Hz), 4.77 (1H, d, J=17.3 Hz), 4.51(1H, d, J=17.3 Hz), 3.94-3.82 (1H, m), 3.80 (3H, s), 3.17 (1H, t, J=12.5Hz), 3.08-2.98 (2H, m), 2.72-2.64 (1H, m), 1.92-1.80 (2H, m), 0.80 (3H,t, J=7.4 Hz)

MS: 489 (M+H)⁺

Reference Example 143 4-nitrophenyl6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate(compound S143)

To the compound S140A (2.69 g) in tetrahydrofuran (160 ml) solution, a1.59M hexane solution of n-butyllithium (3.7 ml) was added at of −78° C.and the mixture was stirred at that temperature for 20 minutes.

Next, p-nitrophenyl chlorocarbonate (1.3 g) in tetrahydrofuran (10 ml)solution was added to the reaction solution at −78° C. and the mixturewas stirred at that temperature for 1 hour. Saturated potassiumhydrogensulfate aqueous solution was added to the reaction solution,tetrahydrofuran was distilled off in vacuo, and the remaining aqueoussolution was extracted with ethyl acetate. The organic layer was washedwith saturated saline, dried over with anhydrous sodium sulfate, andconcentrated to obtain the title compound as a crude product (4.05 g).

Reference Example 144 tert-butylrel-(1R,6R)-5-[1-({[4-(2,4,6-trimethoxybenzyl)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-benzyloxybenzoate(compound S144)

Instead of the starting material of Reference Example 142A, that is, thecompound S141A, the compound S143 was used, while instead of thecompound S83, the compound S89 was used for the similar procedure as inReference Example 142A to obtain the title compound.

NMR (CDCl₃): δ9.4 (1H, d, J=7.7 Hz), 7.6 (1H, d, J=2.4 Hz), 7.48-7.44(2H, m), 7.40-7.35 (2H, m), 7.34-7.28 (2H, m), 7.17 (1H, dd, J=8.8, 2.6Hz), 6.95-6.88 (2H, m), 6.74 (1H, d, J=8.8 Hz), 6.07 (2H, s), 5.3 (1H,d, J=17.4 Hz), 5.11 (2H, s), 4.82-4.70 (2H, m), 4.32 (1H, d, J=13.7 Hz),4.19 (1H, d, J=13.7 Hz), 3.83 (3H, s), 3.76 (3H, s), 3.69 (6H, s),3.58-3.45 (1H, m), 3.1 (1H, dd, J=14.0, 4.3 Hz), 3.05-2.99 (2H, m), 2.37(1H, dd, J=13.8, 9.5 Hz), 1.90-1.75 (2H, m), 1.51 (9H, s), 0.89 (3H, t,J=7.3 Hz)

Reference Example 145 tert-butylrel-(1R,6R)-5-[1-({[4-(2,4,6-trimethoxybenzyl)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-hydroxybenzoate(compound S145)

To the compound S144 (315 mg) in tetrahydrofuran (4 ml) solution,platinum oxide (40 mg) was added and the mixture was stirred underhydrogen atmosphere at room temperature for 18 hours. The insolublecompound was filtered out, then the filtrate was concentrated. Theresidue was purified by silica gel column chromatography(diethylether/ethyl acetate=10/1) to obtain the title compound (186 mg).

NMR (CDCl₃): δ10.97 (1H, s), 9.41 (1H, d, J=7.7 Hz), 7.67 (1H, d, J=2.2Hz), 7.34 (1H, dd, J=8.6, 2.2 Hz), 7.17 (1H, dd, J=8.7, 2.5 Hz),6.95-6.89 (2H, m), 6.74 (1H, d, J=8.7 Hz), 6.07 (2H, s), 5.32 (1H, d,J=17.4 Hz), 4.80-4.70 (2H, m), 4.33 (1H, d, J=13.7 Hz), 4.19 (1H, d,J=13.7 Hz), 3.83 (3H, s), 3.76 (3H, s), 3.7 (6H, s), 3.60-3.46 (1H, m),3.1 (1H, dd, J=13.9, 4.5 Hz), 3.05-2.97 (2H, m), 2.38 (1H, dd, J=13.8,9.5 Hz), 1.89-1.70 (2H, m), 1.61 (9H, s), 0.89 (3H, t, J=7.2 Hz)

Reference Example 146 tert-butylrel-(1R,6R)-5-[1-({[4-(2,4,6-trimethoxybenzyl)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-methoxybenzoate(compound S146)

To the compound S145 (315 mg) in N,N-dimethylformamide (2 ml) solution,methyl iodide (0.06 ml) and potassium carbonate (18 mg) were added andthe mixture was stirred at room temperature for 3 hours. The reactionsolution was diluted with ethyl acetate, successively washed withsaturated sodium thiosulfate aqueous solution, saturated potassiumhydrogensulfate aqueous solution, and saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=2/3) to obtainthe title compound (85 mg).

NMR (CDCl₃): δ9.41 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=2.4 Hz), 7.35 (1H,dd, J=8.6, 2.4 Hz), 7.17 (1H, dd, J=8.7, 2.5 Hz), 6.93-6.88 (2H, m),6.74 (1H, d, J=8.7 Hz), 6.07 (2H, s), 5.01 (1H, d, J=17.4 Hz), 4.82-4.72(2H, m), 4.31 (1H, d, J=13.7 Hz), 4.19 (1H, d, J=13.7 Hz), 3.86 (3H, s),3.83 (3H, s), 3.76 (3H, s), 3.7 (6H, s), 3.58-3.46 (1H, m), 3.1 (1H, dd,J=14.0, 4.4 Hz), 3.05-2.98 (2H, m), 2.37 (1H, dd, J=13.9, 9.3 Hz),1.91-1.74 (2H, m), 1.58 (9H, s), 0.89 (3H, t, J=7.3 Hz)

Example 158rel-(1R,6R)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-hydroxybenzoicacid (compound 158)

Instead of the starting material of Example 91, that is, the compoundS142A, the compound S145 was used for the similar procedure as inExample 91 to obtain the title compound.

NMR (DMSO-d₆): δ9.37 (1H, d, J=7.3 Hz), 7.65 (1H, d, J=3.6 Hz), 7.62(1H, d, J=2.3 Hz), 7.32 (1H, d, J=2.6 Hz), 7.26 (1H, dd, J=8.8, 2.6 Hz),7.23-7.18 (1H, m), 6.99 (1H, d, J=8.8 Hz), 6.70 (1H, d, J=8.4 Hz), 4.76(1H, d, J=17.2 Hz), 4.57 (1H, q, J=7.3 Hz), 4.47 (1H, d, J=17.2 Hz),3.89-3.78 (1H, m), 3.78 (3H, s), 3.14 (1H, t, J=12.6 Hz), 3.04-2.93 (2H,m), 2.68-2.61 (1H, m), 1.84-1.66 (2H, m), 0.80 (3H, t, J=7.2 Hz)

MS: 504 (M+H)⁺

Example 159rel-(1R,6R)-5-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-methoxybenzoicacid (compound 159)

Instead of the starting material of Example 91, that is, the compoundS142A, the compound S146 was used for the similar procedure as inExample 91 to obtain the title compound.

NMR (DMSO-d₆): δ12.60 (1H, brs), 9.39 (1H, d, J=7.4 Hz), 7.66 (1H, d,J=3.6 Hz), 7.54 (1H, d, J=2.2 Hz), 7.43 (1H, dd, J=8.6, 2.2 Hz), 7.32(1H, d, J=2.6 Hz), 7.26 (1H, dd, J=8.8, 2.6 Hz), 7.08 (1H, d, J=8.6 Hz),7.00 (1H, d, J=8.8 Hz), 4.73 (1H, d, J=17.0 Hz), 4.64 (1H, q, J=7.4 Hz),4.48 (1H, d, J=17.0 Hz), 3.90-3.75 (1H, m), 3.80 (3H, s), 3.78 (3H, s),3.15 (1H, t, J=12.8 Hz), 3.03-2.92 (2H, m), 2.65 (1H, dd, J=14.3, 9.4Hz), 1.86-1.68 (2H, m), 0.82 (3H, t, J=7.3 Hz)

MS: 518 (M+H)⁺

Example 160rel-(1R,6R)-3-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-hydroxybenzoicacid (compound 160)

Instead of the starting material of Reference Example 144, that is, thecompound S89, the compound S88 was used for the similar procedure as inReference Example 144, Reference Example 145, and Example 158 to obtainthe title compound.

NMR (DMSO-d₆): δ9.76 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=3.5 Hz), 7.58(1H, d, J=7.5 Hz), 7.32 (1H, d, J=2.6 Hz), 7.26 (1H, dd, J=8.7, 2.6 Hz),7.01-6.98 (2H, m), 6.51 (1H, t, J=7.5 Hz), 4.86-4.78 (2H, m), 4.44 (1H,d, J=17.2 Hz), 3.88-3.78 (1H, m), 3.78 (3H, s), 3.14 (1H, t, J=12.6 Hz),3.03-2.92 (2H, m), 2.69-2.61 (1H, m), 1.90-1.70 (2H, m), 0.77 (3H, t,J=7.3 Hz)

Example 161rel-(1R,6R)-3-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-methoxybenzoicacid (compound 161)

Instead of the starting material of Reference Example 144, that is, thecompound S89, the compound S88 was used for the similar procedure as inReference Example 144, Reference Example 145, Reference Example 146, andExample 159 to obtain the title compound.

NMR (DMSO-d₆): δ9.53 (1H, d, J=8.4 Hz), 7.68 (1H, d, J=3.5 Hz), 7.32(1H, d, J=2.6 Hz), 7.25 (1H, dd, J=8.7, 2.6 Hz), 7.13 (1H, d, 6.99 (1H,d, J=8.8 Hz), 6.96 (1H, d, J=7.4 Hz), 6.84 (1H, t, J=7.4 Hz), 4.95-4.88(1H, m), 4.78 (1H, d, J=17.2 Hz), 4.47 (1H, d, J=17.2 Hz), 3.91-3.78(1H, m), 3.81 (3H, s), 3.78 (3H, s), 3.15 (1H, t, J=12.4 Hz), 3.08-2.94(2H, m), 2.69-2.63 (1H, m), 1.79-1.63 (2H, m), 0.81 (3H, t, J=7.4 Hz)

MS: 518 (M+H)⁺

Example 162rel-(1R,6R)-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-methoxybenzoicacid (compound 162)

Instead of the starting material of Reference Example 144, that is, thecompound S89, the compound S78 was used for the similar procedure as inReference Example 144, Reference Example 146, and Example 159 to obtainthe title compound.

NMR (DMSO-d₆): δ12.47 (1H, brs), 9.42 (1H, d, J=7.5 Hz), 7.68 (1H, d,J=3.7 Hz), 7.59 (1H, d, J=8.1 Hz), 7.33 (1H, d, J=2.6 Hz), 7.27 (1H, dd,J=8.8, 2.6 Hz), 7.07 (1H, s), 7.00 (1H, d, J=8.8 Hz), 6.90 (1H, d, J=8.1Hz), 4.75-4.70 (2H, m), 4.50 (1H, d, J=17.1 Hz), 3.92-3.83 (1H, m), 3.80(3H, s), 3.79 (3H, s), 3.17 (1H, t, J=12.9 Hz), 3.08-2.95 (2H, m), 2.66(1H, dd, J=14.5, 9.1 Hz), 1.85-1.74 (2H, m), 0.86 (3H, t, J=7.2 Hz)

MS: 518 (M+H)⁺

Example 163rel-(1R,6S)-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-methoxybenzoicacid (compound 163)

Instead of the starting material of Reference Example 144, that is, thecompound S89, the compound S78 was used for the similar procedure as inReference Example 144, Reference Example 146, and Example 159 to obtainthe title compound.

NMR (DMSO-d₆): δ12.48 (1H, br), 9.40 (1H, d, J=7.5 Hz), 7.66 (1H, d,J=3.7 Hz), 7.61 (1H, d, J=7.9 Hz), 7.34 (1H, d, J=1.9 Hz), 7.27 (1H, dd,J=8.7, 1.9 Hz), 7.06 (1H, s), 7.01 (1H, d, J=8.7 Hz), 6.92 (1H, d, J=7.9Hz), 4.77-4.72 (2H, m), 4.53 (1H, d, J=17.0 Hz), 3.93-3.84 (1H, m), 3.81(3H, s), 3.79 (3H, s), 3.13 (1H, t, J=12.7 Hz), 3.05-2.96 (2H, m), 2.65(1H, dd, J=14.3, 9.0 Hz), 1.84-1.75 (2H, m), 0.86 (3H, t, J=7.1 Hz)

MS: 518 (M+H)⁺

Reference Example 1476-(5-chloro-2-methoxybenzyl)-N-(3-chlorophenyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxamide(compound S147)

To the compound S140A (150 mg) in tetrahydrofuran (8 ml) solution 1, a1.59M hexane solution of n-butyllithium (0.2 ml) was added at −78° C.and the mixture was stirred at that temperature for 20 minutes. Next, asolution of bis(trichloromethyl)carbonate in tetrahydrofuran 1M solution(0.34 ml) was added to the reaction solution at −78° C. and the mixturewas stirred at that temperature for 45 minutes. After this,3-chloroaniline (0.2 ml) was added to the reaction solution at −78° C.and the mixture was stirred and warmed to 0° C. over 3 hours. Saturatedpotassium hydrogensulfate aqueous solution was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was successively washed with saturated saline and distilled water,dried over with anhydrous sodium sulfate, then concentrated. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=2/3 to 1/2) to obtain the title compound (56.8 mg).

NMR (CDCl₃): δ11.29 (1H, s), 7.65 (1H, s), 7.38 (1H, d, J=8.0 Hz),7.30-7.22 (1H, m), 7.2 (1H, dd, J=8.8, 2.6 Hz), 7.08 (1H, d, J=8.0 Hz),6.96 (1H, d, J=2.6 Hz), 6.77 (1H, d, J=8.8 Hz), 6.07 (2H, s), 5.37 (1H,d, J=17.3 Hz), 4.84 (1H, d, J=13.8 Hz), 4.33 (1H, d, J=17.3 Hz), 4.32(1H, d, J=13.8 Hz), 3.82 (3H, s), 3.79 (3H, s), 3.7 (6H, s), 3.69-3.59(1H, m), 3.19-3.00 (3H, m), 2.44 (1H, dd, J=13.9, 8.8 Hz)

Example 1646-(5-chloro-2-methoxybenzyl)-N-(3-chlorophenyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 164)

To the compound S147 (50 mg), 1M hydrogen chloride/acetic acid solution(1 ml) was added and the mixture was stirred at room temperature for 24hours. The reaction solution was concentrated, then the residue waspurified by florisil column chromatography (ethyl acetate) and the elutewas concentrated. The residue was recrystallized from hexane/ethylacetate to obtain the title compound (18.2 mg).

NMR (CDCl₃): δ11.28 (1H, s), 7.66 (1H, t, J=2.0 Hz), 7.38 (1H, ddd,J=8.1, 2.0, 0.9 Hz), 7.25 (1H, t, J=8.1 Hz), 7.23 (1H, dd, J=8.8, 2.6Hz), 7.16 (1H, d, J=2.6 Hz), 7.10 (1H, ddd, J=8.1, 2.0, 0.9 Hz), 6.82(1H, d, J=8.8 Hz), 5.93 (1H, br), 5.44 (1H, d, J=17.4 Hz), 4.1 (1H, d,J=17.4 Hz), 3.85 (3H, s), 3.84-3.75 (1H, m), 3.41-3.35 (2H, m), 3.22(1H, dd, J=13.9, 5.6 Hz), 2.65 (1H, dd, J=13.9, 8.0 Hz)

MS: 436 (M+H)⁺

Instead of the starting material compound of Reference Example 147, thatis, 3-chloroaniline, the aniline derivatives shown in Table X were usedfor the similar procedure as in Reference Example 147 and Example 164 toobtain the compounds of Example 165 to Example 172. Note that theaniline derivatives shown in Table X are commercially availablecompounds or compounds obtained by derivation from commerciallyavailable compounds by known methods.

TABLE X Aniline derivative Ex. no. used as material Ex. 165

Ex. 166

Ex. 167

Ex. 168

Ex. 169

Ex. 170

Ex. 171

Ex. 172

Example 1656-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-[4-(trifluoromethyl)phenyl]-1,4-diazepan-1-carboxamide(compound 165)

NMR (CDCl₃): δ11.45 (1H, s), 7.67 (2H, d, J=8.7 Hz), 7.59 (2H, d, J=8.7Hz), 7.24 (1H, dd, J=8.7, 2.6 Hz), 7.17 (1H, d, J=2.6 Hz), 6.83 (1H, d,J=8.7 Hz), 5.86 (1H, br), 5.46 (1H, d, J=17.4 Hz), 4.22 (1H, d, J=17.4Hz), 3.89-3.77 (1H, m), 3.86 (3H, s), 3.41-3.38 (2H, m), 3.23 (1H, dd,J=13.9, 5.5 Hz), 2.66 (1H, dd, J=13.9, 7.9 Hz)

MS: 470 (M+H)⁺

Example 1666-(5-chloro-2-methoxybenzyl)-N-(4-methoxyphenyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 166)

NMR (CDCl₃): δ11.04 (1H, s), 7.43 (2H, d, J=8.9 Hz), 7.23 (1H, dd,J=8.8, 2.6 Hz), 7.16 (1H, d, J=2.6 Hz), 6.87 (2H, d, J=8.9 Hz), 6.82(1H, d, J=8.8 Hz), 5.81 (1H, br), 5.48 (1H, d, J=17.5 Hz), 4.19 (1H, d,J=17.5 Hz), 3.85 (3H, s), 3.84-3.72 (1H, m), 3.8 (3H, s), 3.40-3.36 (2H,m), 3.22 (1H, dd, J=14.0, 5.5 Hz), 2.65 (1H, dd, J=14.0, 8.1 Hz)

MS: 432 (M+H)⁺

Example 1676-(5-chloro-2-methoxybenzyl)-N-(6-chloro-3-pyridyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 167)

NMR (DMSO-d₆): δ11.11 (1H, s), 8.57 (1H, d, J=2.7 Hz), 8.07 (1H, dd,J=8.7, 2.7 Hz), 7.75 (1H, d, J=3.5 Hz), 7.49 (1H, d, J=8.7 Hz), 7.36(1H, d, J=2.5 Hz), 7.27 (1H, dd, J=8.7, 2.5 Hz), 7.01 (1H, d, J=8.7 Hz),4.77 (1H, d, J=17.3 Hz), 4.65 (1H, d, J=17.3 Hz), 4.02-3.92 (1H, m),3.79 (3H, s), 3.22 (1H, t, J=12.6 Hz), 3.06-2.99 (2H, m), 2.67 (1H, dd,J=14.4, 9 Hz)

MS: 437 (M+H)⁺

Example 1684-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)benzoicacid (compound 168)

NMR (DMSO-d₆): δ12.68 (1H, br), 11.25 (1H, s), 7.91 (2H, d, J=8.6 Hz),7.75 (1H, d, J=3.9 Hz), 7.65 (2H, d, J=8.6 Hz), 7.36 (1H, d, J=2.6 Hz),7.27 (1H, dd, J=8.8, 2.6 Hz), 7.01 (1H, d, J=8.8 Hz), 4.77 (1H, d,J=17.3 Hz), 4.64 (1H, d, J=17.3 Hz), 4.00-3.90 (1H, m), 3.79 (3H, s),3.24 (1H, t, J=12.6 Hz), 3.07-2.98 (2H, m), 2.67 (1H, dd, J=14.4, 9.0Hz)

MS: 446 (M+H)⁺

Example 1693-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)benzoicacid (compound 169)

NMR (DMSO-d₆): δ11.09 (1H, s), 8.07 (1H, s), 7.74 (1H, d, J=3.7 Hz),7.68-7.62 (2H, m), 7.40-7.35 (2H, m), 7.27 (1H, dd, J=8.8, 2.7 Hz), 7.01(1H, d, J=8.8 Hz), 4.78 (1H, d, J=17.4 Hz), 4.62 (1H, d, J=17.4 Hz),3.99-3.88 (1H, m), 3.79 (3H, s), 3.24 (1H, t, J=12.5 Hz), 3.06-2.97 (2H,m), 2.67 (1H, dd, J=14.3, 9.0 Hz)

MS: 446 (M+H)⁺

Example 1702-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)benzoicacid (compound 170)

NMR (DMSO-d₆): δ8.20 (1H, d, J=8.2 Hz), 7.94 (1H, d, J=7.8 Hz), 7.71(1H, d, J=4.1 Hz), 7.40-7.32 (2H, m), 7.26 (1H, dd, J=8.7, 2.6 Hz),7.06-6.98 (2H, m), 4.64 (1H, d, J=17.1 Hz), 4.58 (1H, d, J=17.1 Hz),3.87-3.79 (1H, m), 3.80 (3H, s), 3.15 (1H, t, J=12.9 Hz), 3.05-2.95 (2H,m), 2.63 (1H, dd, J=14.3, 9.5 Hz)

MS: 446 (M+H)⁺

Example 171N-(3-aminophenyl)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 171)

NMR (DMSO-d₆): δ10.91 (1H, s), 7.72 (1H, d, J=3.6 Hz), 7.34 (1H, d,J=2.6 Hz), 7.26 (1H, dd, J=8.8, 2.6 Hz), 7.00 (1H, d, J=8.8 Hz), 6.94(1H, t, J=8.0 Hz), 6.79 (1H, s), 6.59 (1H, d, J=8 Hz), 6.30 (1H, d, J=8Hz), 5.13 (2H, brs), 4.80 (1H, d, J=17.2 Hz), 4.58 (1H, d, J=17.2 Hz),3.98-3.87 (1H, m), 3.79 (3H, s), 3.21 (1H, t, J=12.9 Hz), 3.06-2.94 (2H,m), 2.66 (1H, dd, J=14.3, 8.9 Hz)

MS: 417 (M+H)⁺

Example 172N-(4-aminophenyl)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 172)

NMR (DMSO-d₆): δ10.7 (1H, s), 7.71 (1H, d, J=3.6 Hz), 7.34 (1H, d, J=2.6Hz), 7.26 (1H, dd, J=8.8, 2.6 Hz), 7.12 (2H, d, J=8.7 Hz), 7.00 (1H, d,J=8.8 Hz), 6.51 (2H, d, J=8.7 Hz), 4.96 (2H, brs), 4.80 (1H, d, J=17.2Hz), 4.57 (1H, d, J=17.2 Hz), 3.97-3.86 (1H, m), 3.79 (3H, s), 3.19 (1H,t, J=12.9 Hz), 3.06-2.93 (2H, m), 2.65 (1H, dd, J=14.3, 8.9 Hz)

MS: 417 (M+H)⁺

Reference Example 148 tert-butyl2-(3-chlorobenzyl)-3-{[(4-nitrophenyl)sulfonyl]amino}-3-oxopropylcarbamate(compound S148)

To the compound S33 (530 mg) in N,N-dimethylformamide (10 ml) solution,4-nitrobenzenesulfonamide (512 mg), 4-dimethylaminopyridine (310 mg),and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (486 mg)were added and the mixture was stirred at room temperature for 17 hours.The reaction solution was concentrated, then the residue was dilutedwith chloroform and saturated sodium hydrogencarbonate aqueous solution.The organic layer was separated, successively washed with saturatedammonium chloride aqueous solution and saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was dried invacuo to obtain the title compound (1.19 g).

Reference Example 149N-[3-amino-2-(3-chlorobenzyl)propanoyl]-4-nitrobenzenesulfonamidehydrochloride (compound S149)

A mixture of the compound S148 (1.19 g) and 1N hydrogen chloride/aceticacid solution (12 ml) were stirred at room temperature for 2 hours. Thereaction solution was concentrated, chloroform and 1N sodium hydroxideaqueous solution were added, the pH of the aqueous layer was made 5, andthe organic layer was separated. The precipitate of the organic layerwas collected by filtration to obtain the title compound (444 mg).

Reference Example 1502-bromo-N-(2-(3-chlorobenzyl)-3-{[(4-nitrophenyl)sulfonyl]amino}-3-oxopropyl)acetoamide(compound S150)

To the compound S149 (428 mg) in chloroform (8.6 ml) solution, 2N sodiumhydroxide aqueous solution (2.0 ml) and bromoacetyl chloride (0.12 ml)were added and the mixture was stirred at room temperature for 2 hours.Distilled water was added to the reaction solution, then the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, andconcentrated to obtain the title compound (299 mg).

NMR (DMSO-d₆): δ8.40-8.25 (3H, m), 8.01 (2H, d, J=8.7 Hz), 7.22-6.89(4H, m), 3.77 (2H, s), 3.19-3.07 (2H, m), 2.99-2.85 (1H, m), 2.72-2.60(2H, m)

Example 1736-(5-chlorobenzyl)-4-[(4-nitrophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 173)

To the compound S150 (295 mg) in N,N-dimethylformamide (29 ml) solution,sodium hydride (60% mineral oil dispersion) (23 mg) was added and themixture was stirred at 60° C. for 17 hours. The reaction solution wasconcentrated, ethyl acetate and saturated ammonium chloride aqueoussolution were added, and the organic layer was separated. The organiclayer was washed with saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was purified by silica gelcolumn chromatography (chloroform/ethyl acetate=1/2) to obtain the titlecompound (41.6 mg).

NMR (DMSO-d₆): δ8.44 (2H, d, J=8.9 Hz), 8.20 (2H, d, J=8.9 Hz),7.91-7.87 (1H, br), 7.31-7.18 (3H, m), 7.18 (1H, d, J=7.3 Hz), 4.95 (1H,d, J=17.5 Hz), 4.57 (1H, d, J=17.5 Hz), 3.88-3.71 (1H, m), 3.09-3.01(2H, m), 2.94 (1H, dd, J=14.5, 5.4 Hz), 2.55-2.40 (1H, m)

MS: 438 (M+H)⁺

Example 1746-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-6-methyl-1,4-diazepan-2,5-dione(compound 176)

Instead of the starting material of Reference Example 117, that is, thecompound S6, the compound S44 was used for the similar procedure as withReference Example 117 and Reference Example 122 and Example 1 to obtainthe title compound.

NMR (CDCl₃): δ7.97 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 7.20 (1H,dd, J=8.7, 2.5 Hz), 6.98 (1H, d, J=2.5 Hz), 6.80 (1H, d, J=8.7 Hz),6.05-5.99 (1H, br), 4.68 (1H, d, J=15.3 Hz), 4.47 (1H, d, J=15.3 Hz),3.78 (3H, s), 3.23 (1H, d, J=6.3 Hz), 3.21 (1H, d, J=6.3 Hz), 3.11 (1H,d, J=13.8 Hz), 2.79 (1H, d, J=13.8 Hz), 1.2 (3H, s)

MS: 471 (M+H)⁺

Example 1756-(5-chloro-2-methoxybenzyl)-6-fluoro-3,7-dioxo-N-[(1R)-1-phenylpropyl]-1,4-diazepan-1-carboxamide(compound 175)

To the compound S51 (157 mg) in tetrahydrofuran (1.6 ml) solution,N,N-diisopropylethylamine (83 μl) and 2,4,6-trichlorobenzoylchloride (68μl) were added and the mixture was stirred at room temperature for 1.5hours, then 4-dimethylaminopyridine (176 mg) andN-[(1R)-1-phenylpropyl]urea (77 mg) were added and the mixture wasstirred at room temperature for 3 hours. Distilled water was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was successively washed with saturated potassiumhydrogensulfate aqueous solution, distilled water, saturated sodiumhydrogencarbonate aqueous solution, and saturated saline, dried overwith anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=5/1).The thus obtained tert-butyl2-(5-chloro-2-methoxybenzyl)-2-fluoro-3-oxo-3-[({[(1R)-1-phenylpropyl]amino}carbonyl)amino]propylcarbamate (74 mg) was used instead of the starting material compound ofReference Example 149, that is, the compound S148, for the similarprocedure as with Reference Example 149, Reference Example 150, andExample 173 to obtain the title compound.

NMR (CDCl₃): δ9.47-9.39 (1H, br), 7.38-7.18 (7H, m), 6.85 (0.5H, d,J=8.7 Hz), 6.77 (0.5H, d, J=8.6 Hz), 5.79-5.71 (1H, br), 4.94 (0.5H, d,J=15.7 Hz), 4.84-4.76 (1.5H, m), 4.51 (0.5H, dd, J=15.8, 3.0 Hz), 4.35(0.5H, dd, J=15.8, 2.5 Hz), 3.85 (1.5H, s), 3.81-3.64 (1H, m), 3.69(1.5H, s), 3.55-3.17 (3H, m), 1.98-1.78 (2H, m), 0.96-0.87 (3H, m)

MS: 462 (M+H)⁺

Example 1763-[1-({[6-(5-chloro-2-methoxybenzyl)-6-fluoro-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 176)

(Step 1) To the compound S51 (157 mg) in tetrahydrofuran (1.6 ml)solution, N,N-diisopropylethylamine (83 μl) and2,4,6-trichlorobenzoylchloride (68 μm) were added and the mixture wasstirred at room temperature for 1.5 hours, then concentrated. To theresidue, toluene (1.5 ml), 4-dimethylaminopyridine (176 mg), andtert-butyl 3-{1-[(aminocarbonyl)amino]propyl}benzoate (121 mg) obtainedby using the compound S87 instead of the starting material compound ofReference Example 72, that is, (1R)-1-phenylethylamine, for the similarprocedure as in Reference Example 72 were added and the mixture wasstirred at room temperature for 3 hours. Distilled water was added tothe reaction solution, then the mixture was extracted with ethylacetate. The organic layer was successively washed with saturatedpotassium hydrogensulfate aqueous solution, distilled water, saturatedsodium hydrogencarbonate aqueous solution, and saturated saline, driedover with anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=3/1)to obtain tert-butyl3-[6-(5-chloro-2-methoxybenzyl)-1-ethyl-6-fluoro-11,11-dimethyl-3,5,9-trioxo-10-oxa-2,4,8-triazadodec-1-yl]benzoate(146 mg). (Step 2) To the obtained tert-butyl3-[6-(5-chloro-2-methoxybenzyl)-1-ethyl-6-fluoro-11,11-dimethyl-3,5,9-trioxo-10-oxa-2,4,8-triazadodec-1-yl]benzoicacid (108 mg), a 1M hydrochloric acid/acetic acid solution (1 ml) wasadded and the mixture was stirred at room temperature for 3 hours.Diethyl ether was added to the reaction solution, and the precipitatedsolid was collected by filtration. To the solid collected by filtration,tetrahydrofuran (1.6 ml), 1N sodium hydroxide aqueous solution (0.43ml), and di-tert-butyl dicarbonate (47 mg) were added and the mixturewas stirred at room temperature for 3 hours. Saturated potassiumhydrogensulfate aqueous solution was added to the reaction solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated saline, dried over with anhydrous sodium sulfate,then concentrated. Ethyl acetate/tetrahydrofuran/hexane was added to theresidue and the precipitated solid was collected by filtration. To theobtained solid in DMF (1.3 ml) solution, 4-dimethylaminopyridine (20mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32mg), and benzyl alcohol (12 μl) were added and the mixture was stirredat room temperature for 5 hours. Saturated potassium hydrogensulfateaqueous solution was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The organic layer was successively washedwith distilled water, saturated sodium hydrogencarbonate aqueoussolution, and saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=4/1) to obtain benzyl3-[6-(5-chloro-2-methoxybenzyl)-1-ethyl-6-fluoro-11,11-dimethyl-3,5,9-trioxo-10-oxa-2,4,8-triazadodec-1-yl]benzoate(51 mg).

(Step 3) The obtained benzyl3-[6-(5-chloro-2-methoxybenzyl)-1-ethyl-6-fluoro-11,11-dimethyl-3,5,9-trioxo-10-oxa-2,4,8-triazadodec-1-yl]benzoatewas used instead of the starting material compound of Reference Example149, that is, the compound S148, for the similar procedure as inReference Example 149, Reference Example 150, and Example 173 to obtainbenzyl3-[1-({[6-(5-chloro-2-methoxybenzyl)-6-fluoro-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate.

(Step 4) To the obtained benzyl3-[1-({[6-(5-chloro-2-methoxybenzyl)-6-fluoro-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(20 mg) in tetrahydrofuran (1 ml) solution, platinum oxide (6 mg) wasadded and the mixture was stirred under hydrogen atmosphere at roomtemperature for 1.5 hours. Next, the catalyst was filtered out, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (chloroform/ethyl acetate/methanol/acetic acid=8/8/1/0.1)to obtain the title compound (9.3 mg).

NMR (DMSO-d₆): δ13.00-12.89 (1H, br), 9.26 (1H, d, J=7.2 Hz), 8.13-8.07(1H, br), 7.90-7.79 (2H, m), 7.60-7.42 (2H, m), 7.36-7.17 (2H, m), 7.02(0.5H, d, J=8.8 Hz), 6.87 (0.5H, d, J=8.8 Hz), 4.80-4.68 (1H, br), 4.56(0.5H, d, J=15.7 Hz), 4.41 (0.5H, d, J=15.7 Hz), 4.18 (1H, d, J=15.7Hz), 4.02-3.80 (1H, m), 3.74 (1.5H, s), 3.50 (1.5H, s), 3.40-2.82 (3H,m), 1.90-1.71 (2H, m), 0.89-0.75 (3H, m)

MS: 506 (M+H)⁺

Example 177 6-benzyl-4-(4-chlorobenzenesulfonyl)-1,4-diazepan-2,5-dione(compound 177)

N-(tert-butoxycarbonyl)-2-benzyl-β-alanine synthesized by usingbenzaldehyde as the starting material for the similar procedure as inReference Examples 2 to 5, Reference Example 23, and Reference Example33 was used instead of the starting material of Reference Example 148,that is, the compound S33, and 4-chlorobenzenesulfonamide was usedinstead of 4-nitrobenzenesulfonamide for the similar procedure as inReference Example 148 to Reference Example 150 and Example 173 to obtainthe title compound.

NMR (CDCl₃): δ7.96 (2H, d, J=8.6 Hz), 7.51 (2H, d, J=8.6 Hz), 7.32-7.21(3H, m), 7.11 (2H, d, J=6.8 Hz), 5.87 (1H, br), 4.97 (1H, d, J=17.6 Hz),4.42 (1H, d, J=17.6 Hz), 3.39-3.12 (4H, m), 2.55 (1H, dd, J=14.4, 8.9Hz)

MS: 393 (M+H)⁺

Reference Example 151tert-butyl(2R)-3-amino-2-(5-chloro-2-methoxybenzyl)-3-oxopropylcarbamate(compound S151)

(Step 1) To themethyl(2R)-3-amino-2-(5-chloro-2-methoxybenzyl)propanoate tosylate (97.9g), synthesized from the compound S1 as an starting material inaccordance with Japanese Patent Publication (A) No. 2004-300036, intetrahydrofuran (180 ml)/2M sodium hydroxide (125 ml) solution,di-tert-butyl dicarbonate (55 g) was added under ice cooling and themixture was stirred at room temperature for 1 hour. Ethyl acetate wasadded to the reaction solution, and the aqueous layer and the organiclayer were separated. The organic layer was washed with saturatedsaline, dried over with anhydrous sodium sulfate, and concentrated toobtainmethyl(2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoate as a crude product (99.8 g).

(Step 2) To the crude product (99.8 g) of step 1 in methanol (180 ml)solution, an 85% potassium hydroxide (30 g) aqueous solution (90 ml) wasadded under ice cooling and the mixture was stirred at room temperaturefor 1.5 hours. 2N hydrochloric acid (260 ml) was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was recrystallized fromtoluene/hexane to obtain(2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoicacid (73.8 g).

(Step 3) To(2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoicacid (15 g) in tetrahydrofuran (75 ml) solution,1,1′-carbonyldiimidazole (7.8 g) was added under ice cooling and themixture was stirred at room temperature for 1 hour. The reactionsolution was cooled to 0° C., 28% ammonia water (15 ml) was added, andthe mixture was stirred at room temperature for 30 minutes. To thereaction solution, distilled water, ethyl acetate, and tetrahydrofuranwere added, the aqueous layer and the organic layer were separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayer was successively washed with saturated potassium hydrogensulfateaqueous solution and saturated saline, dried over with anhydrous sodiumsulfate, and concentrated until a small amount of ethyl acetateremained. Hexane was added to the concentrated solution, and theprecipitated solid was collected by filtration to obtain the titlecompound (13.5 g).

NMR (DMSO-d₆): δ7.25-7.18 (2H, m), 7.13 (1H, d, J=2.7 Hz), 6.94 (1H, d,J=8.8 Hz), 6.81 (1H, brs), 6.71 (1H, br), 3.76 (3H, s), 3.14-3.02 (1H,m), 2.97-2.85 (1H, m), 2.73-2.52 (3H, m), 1.37 (9H, s)

Reference Example 152tert-butyl(2S)-3-amino-2-(5-chloro-2-methoxybenzyl)-3-oxopropylcarbamate(compound S152)

(Step 1) To the methyl(2S)-3-amino-2-(5-chloro-2-methoxybenzyl)propanoate tosylate (97.9 g),synthesized from the compound S1 as an starting material in accordancewith Japanese Patent Publication (A) No. 2004-300036, in tetrahydrofuran(100 ml)/1M sodium hydroxide (100 ml) solution, di-tert-butyldicarbonate (24 g) was added under ice cooling and the mixture wasstirred at room temperature for 1 hour. Ethyl acetate was added to thereaction solution, and the aqueous layer and the organic layer wereseparated. The organic layer was washed with saturated saline, driedover with anhydrous sodium sulfate, and concentrated to obtainmethyl(2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoateas a crude product (42.9 g).

(Step 2) To the crude product (42.9 g) of step 1 in methanol (100 ml)solution, a 85% potassium hydroxide (13.3 g) aqueous solution (40 ml)was added under ice cooling and the mixture was stirred at roomtemperature for 1.5 hours. 2N hydrochloric acid (110 ml) was added tothe reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue wasrecrystallized from toluene/hexane to obtain(2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoicacid (30.9 g).

(Step 3) To(2S)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoicacid (30 g) in tetrahydrofuran (150 ml) solution,1,1′-carbonyldiimidazole (15.6 g) was added under ice cooling and themixture was stirred at room temperature for 1 hour. The reactionsolution was cooled to 0° C., 28% ammonia water (30 ml) was added, andthe mixture was stirred at room temperature for 30 minutes. Distilledwater and ethyl acetate were added to the reaction solution, the aqueouslayer and the organic layer were separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layer wassuccessively washed with saturated potassium hydrogensulfate aqueoussolution and saturated saline, dried over with anhydrous sodium sulfate,then concentrated. Hexane and ethyl acetate were added to theprecipitated solid and the mixture was stirred in the suspended state atroom temperature. The precipitated solid was collected by filtration toobtain the title compound (29.2 g).

NMR (DMSO-d₆): δ7.25-7.18 (2H, m), 7.13 (1H, d, J=2.7 Hz), 6.94 (1H, d,J=8.8 Hz), 6.81 (1H, brs), 6.71 (1H, br), 3.76 (3H, s), 3.14-3.02 (1H,m), 2.97-2.85 (1H, m), 2.73-2.52 (3H, m), 1.37 (9H, s)

Reference Example 153 tert-butyl4-[(1R,6R)-6-(5-chloro-2-methoxybenzyl)-1-ethyl-11,11-dimethyl-3,5,9-trioxo-10-oxa-2,4,8-triazadodec-1-yl]-2-nitrobenzoate(compound S153)

To the compound S151 (0.88 g) in N,N-dimethylformamide (30 ml) solution,sodium hydride (60% mineral oil dispersion) (102 mg) was added under icecooling and the mixture was stirred at room temperature for 15 minutes.Next, the compound S116 (0.94 g) in tetrahydrofuran (10 ml) solution wasadded to the reaction solution under ice cooling and the mixture wasstirred at that temperature for 1 hour. Saturated potassiumhydrogensulfate aqueous solution was added under ice cooling to thereaction solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate, ethyl acetate:20 to 50%) to obtain the title compound (0.72 g).

NMR (CDCl₃): δ8.75 (1H, d, J=7.1 Hz), 8.02 (1H, s), 7.73-7.69 (2H, m),7.52 (1H, dd, J=7.9, 1.6 Hz), 7.17 (1H, dd, J=8.8, 2.5 Hz), 7.1 (1H, d,J=2.5 Hz), 6.77 (1H, d, J=8.8 Hz), 5.00-4.89 (1H, m), 4.81 (1H, q, J=7.1Hz), 3.81 (3H, s), 3.40-3.30 (2H, m), 2.91-2.69 (3H, m), 1.90-1.82 (2H,m), 1.57 (9H, s), 1.43 (9H, s), 0.96 (3H, t, J=7.3 Hz)

Reference Example 154 tert-butyl4-[(1R,6S)-6-(5-chloro-2-methoxybenzyl)-1-ethyl-11,11-dimethyl-3,5,9-trioxo-10-oxa-2,4,8-triazadodec-1-yl]-2-nitrobenzoate(compound S154)

To the compound S152 (1.08 g) in N,N-dimethylformamide (7 ml) solution,potassium tert-butoxide (350 mg) was added under ice cooling and themixture was stirred at that temperature for 10 minutes. Next, thecompound S116 (1.04 g) in tetrahydrofuran (2.5 ml) solution was added tothe reaction solution under ice cooling and the mixture was stirred atthat temperature for 30 minutes. Saturated potassium hydrogensulfateaqueous solution and distilled water were added under ice cooling to thereaction solution and the mixture was extracted with a mixed solvent ofhexane/ethyl acetate=1/1. The organic layer was successively washed withdistilled water and saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate, 3/2 to 1/1) to obtain thetitle compound (1.56 g).

NMR (CDCl₃): δ8.78 (1H, d, J=7.1 Hz), 8.31 (1H, s), 7.73 (1H, d, J=1.5Hz), 7.67 (1H, d, J=7.9 Hz), 7.56 (1H, dd, J=7.9, 1.5 Hz), 7.18 (1H, dd,J=8.8, 2.5 Hz), 7.11 (1H, d, J=2.5 Hz), 6.78 (1H, d, J=8.8 Hz), 4.9 (1H,br), 4.82 (1H, q, J=7.1 Hz), 3.84 (3H, s), 3.38-3.27 (2H, m), 3.90-2.69(3H, m), 1.91-1.80 (2H, m), 1.54 (9H, s), 1.38 (9H, s), 0.96 (3H, t,J=7.3 Hz)

Reference Example 155 tert-butyl 3-[(1R)-1-isocyanatepropyl]benzoate(compound S155)

To the compound S83 (1 g) in methylene chloride (15 ml)/2M sodiumhydroxide aqueous solution (15 ml) solution, trichloromethylchloroformate (0.31 ml) was added under ice cooling and the mixture wasstirred at that temperature for 20 minutes. The reaction solution wasextracted with methylene chloride. The extract was washed with saturatedsaline, dried over with anhydrous sodium sulfate, and concentrated toobtain the title compound as a crude product (653 mg).

NMR (CDCl₃): δ7.94-7.88 (2H, m), 7.49-7.44 (1H, m), 7.41 (1H, t, J=7.7Hz), 4.6 (1H, t, J=6.6 Hz), 1.93-1.84 (2H, m), 1.61 (9H, s), 0.99 (3H,t, J=7.3 Hz)

Reference Example 156 tert-butyl3-[(1R,6R)-6-(5-chloro-2-methoxybenzyl)-1-ethyl-11,11-dimethyl-3,5,9-trioxo-10-oxa-2,4,8-triazadodec-1-yl]benzoate(compound S156)

To the compound S151 (775 mg) in N,N-dimethylformamide (4 ml) solution,potassium tert-butoxide (254 mg) was added under ice cooling and themixture was stirred at that temperature for 15 minutes.

Next, the compound S155 (653 mg) in tetrahydrofuran (1 ml) solution wasadded to the reaction solution under ice cooling and the mixture wasstirred at that temperature for 30 minutes. Under ice cooling, saturatedpotassium hydrogensulfate aqueous solution was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was successively washed with distilled water and saturated saline,dried over with anhydrous sodium sulfate, and concentrated to obtain thetitle compound as a crude product (1.45 g).

NMR (CDCl₃): δ8.7 (1H, d, J=7.9 Hz), 7.99 (1H, s), 7.9 (1H, s), 7.87(1H, dd, J=7.3, 1.4 Hz), 7.45-7.36 (2H, m), 7.15 (1H, dd, J=8.7, 2.4Hz), 7.09 (1H, d, J=2.4 Hz), 6.74 (1H, d, J=8.7 Hz), 4.96 (1H, br), 4.82(1H, q, J=7.3 Hz), 3.76 (3H, s), 3.39-3.26 (2H, m), 2.93-2.82 (1H, m),2.80-2.64 (2H, m), 1.94-1.80 (2H, m), 1.59 (9H, s), 1.43 (9H, s), 0.92(3H, t, J=7.5 Hz)

Reference Example 157 tert-butyl4-{(1R)-1-[({[(2R)-3-amino-2-(5-chloro-2-methoxybenzyl)propanoyl]amino}carbonyl)amino]propyl}-2-nitrobenzoatehydrochloride (compound S157)

A mixed solution of the compound S153 (58.7 mg) and 1N hydrogenchloride/ethyl acetate solution (0.45 ml) was stirred at roomtemperature for 5 hours. Further, 1N hydrogen chloride/ethyl acetatesolution (0.45 ml) was added to the reaction solution and the mixturewas stirred at room temperature for 3 hours. Next, the reaction solutionwas concentrated, and the residue was washed with ethyl acetate,tetrahydrofuran, and hexane to obtain the title compound (42 mg).

Reference Example 158 tert-butyl4-{(1R)-1-[({[(2R)-3-[(bromoacetyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoyl]amino}carbonyl)amino]propyl}-2-nitrobenzoate(compound S158)

To the compound S157 (0.37 g) in methylene chloride (10 ml)/1N sodiumhydroxide aqueous solution (3 ml) solution, bromoacetyl chloride (126μM) was added under ice cooling and the mixture was stirred at thattemperature for 4.5 hours. Distilled water was added to the reactionsolution, and the mixture was extracted with ethyl acetate. The organiclayer was successively washed with 1N hydrochloric acid and saturatedsaline, dried over with anhydrous sodium sulfate, and concentrated toobtain the title compound (403 mg).

NMR (CDCl₃): δ9.1 (1H, s), 8.81 (1H, d, J=7.2 Hz), 7.71-7.65 (2H, m),7.51 (1H, dd, J=8.0, 1.6 Hz), 7.17 (1H, dd, J=8.8, 2.6 Hz), 7.09 (1H, d,J=2.6 Hz), 6.94 (1H, br), 6.76 (1H, d, J=8.8 Hz), 4.83 (1H, q, J=7.2Hz), 3.85 (2H, s), 3.76 (3H, s), 3.47 (2H, t, J=6.0 Hz), 2.95-2.84 (2H,m), 2.83-2.75 (1H, m), 1.94-1.80 (2H, m), 1.54 (9H, s), 0.96 (3H, t,J=7.3 Hz)

Reference Example 159 tert-butyl4-{(1R)-1-[({[(2S)-3-[(bromoacetyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoyl]amino}carbonyl)amino]propyl}-2-nitrobenzoate(compound S159)

To the compound S154 (1.9 g) in ethyl acetate (11 ml) solution, a 4Nhydrogen chloride/ethyl acetate solution (3.7 ml) was added under icecooling and the mixture was stirred at room temperature for 6 hours.Next, 4M sodium hydroxide aqueous solution (7.4 ml) and bromoacetylchloride (0.25 ml) were added to the reaction solution under ice coolingand the mixture was stirred at that temperature for 30 minutes. Thereaction solution was separated into an aqueous layer and organic layer,and the aqueous layer was extracted with ethyl acetate. The combinedorganic layer was successively washed with 1N hydrochloric acid andsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate, 1/1 to 1/2) to obtain the titlecompound (1.04 g).

NMR (CDCl₃): δ8.78 (1H, d, J=7.0 Hz), 7.72 (1H, d, J=1.5 Hz), 7.66 (1H,d, J=7.8 Hz), 7.54 (1H, dd, J=7.8, 1.5 Hz), 7.2 (1H, dd, J=8.8, 2.6 Hz),7.14 (1H, d, J=2.6 Hz), 6.87 (1H, t, J=5.8 Hz), 6.8 (1H, d, J=8.8 Hz),4.82 (1H, q, J=7.0 Hz), 3.85 (3H, s), 3.8 (2H, s), 3.44 (2H, t, J=5.8Hz), 2.92-2.77 (3H, m), 1.91-1.81 (2H, m), 1.54 (9H, s), 0.97 (3H, t,J=7.4 Hz)

Reference Example 160 tert-butyl3-{(1R)-1-[({[(2R)-3-[(bromoacetyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoyl]amino}carbonyl)amino]propyl}benzoate(compound S160)

To the compound S156 (1.45 g) in ethyl acetate (9 ml) solution, 4Nhydrogen chloride/ethyl acetate solution (3 ml) was added under icecooling and the mixture was stirred at room temperature for 6 hours.Next, a 4M sodium hydroxide aqueous solution (5 ml) was added to thereaction solution under ice cooling, the aqueous layer and the organiclayer were separated, and the aqueous layer was extracted with ethylacetate. To the combined organic layer, saturated sodiumhydrogencarbonate aqueous solution (3 ml) was added, then, under icecooling, bromoacetyl chloride (0.19 ml) was added and the mixture wasstirred at that temperature for 20 minutes. The reaction solution wasseparated into an aqueous layer and organic layer, then the organiclayer was successively washed with saturated sodium hydrogencarbonateaqueous solution, distilled water, and saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate, 1/2 to 1/3) toobtain the title compound (960 mg).

NMR (CDCl₃): δ8.68 (1H, d, J=7.7 Hz), 8.37 (1H, s), 7.93-7.90 (1H, m),7.87 (1H, dt, J=7.7, 1.5 Hz), 7.43 (1H, dt, J=7.7, 1.5 Hz), 7.38 (1H, t,J=7.7 Hz), 7.17 (1H, dd, J=8.7, 2.6 Hz), 7.1 (1H, d, J=2.6 Hz), 6.96(1H, br), 6.75 (1H, d, J=8.7 Hz), 4.83 (1H, q, J=7.7 Hz), 3.85 (2H, s),3.76 (3H, s), 3.54-3.48 (2H, m), 2.91 (1H, dd, J=13.4, 5.8 Hz),2.85-2.77 (1H, m), 2.71 (1H, dd, J=13.4, 6.9 Hz), 1.92-1.83 (2H, m),1.59 (9H, s), 0.93 (3H, t, J=7.3 Hz)

Reference Example 161 tert-butyl4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-nitrobenzoate(compound S161)

To the compound S158 (200 mg) in N,N-dimethylformamide (10 ml) solution,tripotassium phosphate (63 mg) was added under ice cooling and themixture was stirred at 50° C. for 8 hours. Saturated potassiumhydrogensulfate aqueous solution was added to the reaction solution andthe mixture was extracted with a hexane/ethyl acetate=1/1 mixed solvent.The organic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/1 to 1/2) toobtain the title compound (91.8 mg).

NMR (CDCl₃): δ9.57 (1H, d, J=6.8 Hz), 7.72 (1H, d, J=1.5 Hz), 7.69 (1H,d, J=7.9 Hz), 7.55 (1H, dd, J=7.9, 1.5 Hz), 7.22 (1H, dd, J=8.8, 2.6Hz), 7.13 (1H, d, J=2.6 Hz), 6.81 (1H, d, J=8.8 Hz), 5.9 (1H, br), 5.27(1H, d, J=17.3 Hz), 4.82 (1H, q, J=6.8 Hz), 4.11 (1H, d, J=17.3 Hz),3.83 (3H, s), 3.79-3.67 (1H, m), 3.39-3.30 (2H, m), 3.2 (1H, dd, J=13.9,5.1 Hz), 2.62 (1H, dd, J=13.9, 8.4 Hz), 1.95-1.80 (2H, m), 1.55 (9H, s),0.97 (3H, t, J=7.3 Hz)

Reference Example 162 tert-butyl4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-nitrobenzoate(compound S162)

To the compound S159 (10.4 g) in N,N-dimethylformamide (500 ml)solution, tripotassium phosphate (3.3 g) was added under ice cooling andthe mixture was stirred at 60° C. for 5 hours. Saturated potassiumhydrogensulfate aqueous solution and distilled water were added to thereaction solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/2 to only ethylacetate) to obtain the title compound (5.32 g).

NMR (CDCl₃): δ9.56 (1H, d, J=7.0 Hz), 7.73 (1H, d, J=1.5 Hz), 7.69 (1H,d, J=7.8 Hz), 7.56 (1H, dd, J=7.8, 1.5 Hz), 7.22 (1H, dd, J=8.8, 2.6Hz), 7.14 (1H, d, J=2.6 Hz), 6.81 (1H, d, J=8.8 Hz), 5.88 (1H, br), 5.3(1H, d, J=17.4 Hz), 4.84 (1H, q, J=7.0 Hz), 4.19-4.09 (1H, m), 3.84 (3H,s), 3.74-3.65 (1H, m), 3.38-3.30 (2H, m), 3.19 (1H, dd, J=14.0, 5.4 Hz),2.63 (1H, dd, J=14.0, 8.2 Hz), 1.94-1.80 (2H, m), 1.55 (9H, s), 0.95(3H, t, J=7.3 Hz)

Reference Example 163 tert-butyl3-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound S163)

To the compound S160 (955 mg) in N-methyl-2-pyrrolidone (30 ml)solution, tripotassium phosphate (325 mg) was added under ice coolingand the mixture was stirred at 60° C. for 5 hours. Saturated potassiumhydrogensulfate aqueous solution and distilled water were added to thereaction solution and the mixture was extracted with a hexane/ethylacetate=1/1 mixed solvent. The organic layer was washed with saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1/2 to 1/3) to obtain the title compound (410 mg).

NMR (CDCl₃): δ9.53 (1H, d, J=7.4 Hz), 7.91 (1H, t, J=1.6 Hz), 7.87 (1H,dt, J=7.6, 1.6 Hz), 7.45 (1H, dt, J=7.6, 1.6 Hz), 7.37 (1H, t, J=7.6Hz), 7.21 (1H, dd, J=8.8, 2.7 Hz), 7.11 (1H, d, J=2.7 Hz), 6.8 (1H, d,J=8.8 Hz), 5.83 (1H, br), 5.33 (1H, d, J=17.5 Hz), 4.81 (1H, q, J=7.4Hz), 4.07 (1H, d, J=17.5 Hz), 3.82 (3H, s), 3.74-3.64 (1H, m), 3.37-3.29(2H, m), 3.2 (1H, dd, J=14.0, 4.9 Hz), 2.6 (1H, dd, J=14.0, 8.7 Hz),1.95-1.80 (2H, m), 1.59 (9H, s), 0.93 (3H, t, J=7.4 Hz)

Reference Example 164 tert-butyl2-amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound S164)

To the compound S161 (22.1 mg) in acetic acid (1 ml) solution, zincpowder was added and the mixture was stirred at 50° C. for 3 hours. Theinsoluble compound was filtered out, and the filtrate was concentrated.Ethyl acetate was added to the residue, then the insoluble compound wasfiltered out. The filtrate was concentrated to obtain the title compound(19.7 mg).

NMR (CDCl₃): δ9.46 (1H, d, J=7.5 Hz), 7.77 (1H, d, J=8.3 Hz), 7.21 (1H,dd, J=8.3, 2.6 Hz), 7.13 (1H, d, J=2.6 Hz), 6.8 (1H, d, J=8.8 Hz), 6.74(1H, br), 6.58-6.52 (2H, m), 5.36 (1H, d, J=17.4 Hz), 4.66 (1H, q, J=7.5Hz), 4.08 (1H, d, J=17.4 Hz), 3.83 (3H, s), 3.74-3.63 (1H, m), 3.38-3.31(2H, m), 3.17 (1H, dd, J=13.9, 5.3 Hz), 2.6 (1H, dd, J=13.9, 8.4 Hz),1.90-1.74 (2H, m), 1.56 (9H, s), 0.91 (3H, t, J=7.4 Hz)

Reference Example 165 tert-butyl2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound S165)

To the compound S162 (4.5 g) in acetic acid (225 ml) solution, zincpowder (22.5 g) was added and the mixture was stirred at 50° C. for 3hours. The insoluble compound was filtered out, ethyl acetate anddistilled water were added to the filtrate, and the organic layer andthe aqueous layer were separated. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, andconcentrated to obtain the title compound (4.4 g).

NMR (CDCl₃): δ9.43 (1H, d, J=7.8 Hz), 7.79 (1H, d, J=8.6 Hz), 7.21 (1H,dd, J=8.6, 2.6 Hz), 7.12 (1H, d, J=2.6 Hz), 6.8 (1H, d, J=8.8 Hz),6.59-6.53 (2H, m), 5.88 (1H, br), 5.72 (2H, br), 5.37 (1H, d, J=17.5Hz), 4.69 (1H, q, J=7.8 Hz), 4.18-4.08 (1H, m), 3.83 (3H, s), 3.74-3.62(1H, m), 3.32-3.25 (2H, m), 3.18 (1H, dd, J=14.0, 5.3 Hz), 2.59 (1H, dd,J=14.0, 8.4 Hz), 1.90-1.74 (2H, m), 1.56 (9H, s), 0.89 (3H, t, J=7.5 Hz)

Example 178A2-amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 178A)

A mixed solution of the compound S164 (1.38 g) and 1N hydrochloricacid/acetic acid solution (27 ml) was stirred at room temperature for2.5 hours. The reaction solution was concentrated, saturated ammoniumchloride was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was dilutedwith ethyl acetate, then the precipitated crystal was collected byfiltration to obtain the title compound (787 mg).

NMR (DMSO-d₆): δ9.42 (1H, d, J=7.5 Hz), 7.69 (1H, brd, J=3.9 Hz), 7.64(1H, d, J=8.2 Hz), 7.33 (1H, d, J=2.7 Hz), 7.27 (1H, dd, J=8.2, 2.7 Hz),7.01 (1H, d, J=8.9 Hz), 6.64 (1H, d, J=1.4 Hz), 6.44 (1H, dd, J=8.9, 1.4Hz), 4.76 (1H, d, J=17.4 Hz), 4.59-4.48 (2H, m), 3.93-3.82 (1H, m), 3.79(3H, s), 3.15 (1H, t, J=13.0 Hz), 3.04-2.94 (2H, m), 2.70-2.64 (1H, m),1.80-1.67 (2H, m), 0.83 (3H, t, J=7.3 Hz)

MS: 503 (M+H)⁺

Melting point: 137-139° C.

Example 178B2-amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid 2-propanol solvate (compound 178B)

The compound 178A (500 mg) was heated and completely dissolved in2-propanol-water (95:5) (2.5 ml), then the solution was allowed to coolto room temperature for recrystallization to obtain the title compound(370 mg).

NMR (DMSO-d₆): δ9.43 (1H, d, J=7.6 Hz), 7.7 (1H, d, J=3.6 Hz), 7.64 (1H,d, J=8.3 Hz), 7.34 (1H, d, J=2.7 Hz), 7.27 (1H, dd, J=8.3, 2.7 Hz), 7.01(1H, d, J=8.9 Hz), 6.64 (1H, d, J=1.3 Hz), 6.43 (1H, dd, J=8.9, 1.3 Hz),4.76 (1H, d, J=17.1 Hz), 4.59-4.48 (2H, m), 4.35 (1H, br), 3.93-3.82(1H, m), 3.81-3.71 (1H, m), 3.79 (3H, s), 3.16 (1H, t, J=13.0 Hz),3.07-2.95 (2H, m), 2.66 (1H, dd, J=14.3, 9.4 Hz), 1.83-1.65 (2H, m),1.03 (6H, d, J=6.1 Hz), 0.83 (3H, t, J=7.2 Hz)

MS: 503 (M+H)⁺

Melting point: 142-145° C.

Example 179A2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid hydrochloride (compound 179A)

A mixed solution of the compound S165 (4.36 g) and an 1N hydrochloricacid/acetic acid solution (87 ml) was stirred at room temperature for 2hours. Ethyl acetate was added to the reaction solution, and theprecipitated crystal was collected by filtration to obtain the titlecompound (3.25 g).

NMR (DMSO-d₆): δ9.41 (1H, d, 7.7 Hz), 7.67 (1H, br), 7.66 (1H, d, 8.3Hz), 7.33 (1H, d, 2.7 Hz), 7.27 (1H, dd, 8.8, 2.7 Hz), 7.01 (1H, d, 8.8Hz), 6.65 (1H, s), 6.47 (1H, d, 8.3 Hz), 4.78 (1H, d, 17.3), 4.60-4.49(2H, m), 3.93-3.84 (1H, m), 3.79 (3H, s), 3.13 (1H, t, 12.6 Hz),3.05-2.93 (2H, m), 2.70-2.62 (1H, m), 1.79-1.67 (2H, m), 0.83 (3H, t,7.3 Hz)

MS: 503 (M+H)⁺

Example 179B2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 150)

To the compound 179A (750 mg), 2-propanol (7.5 ml) was added to obtain asuspension. This was stirred at 60° C. for 1 hour. The mixture wascooled to room temperature, the ice-cooled for 30 minutes. Theprecipitated solid was collected by filtration to obtain the titlecompound (674 mg).

NMR (DMSO-d₆): δ9.41 (1H, d, 7.7 Hz), 7.67 (1H, br), 7.66 (1H, d, 8.2Hz), 7.33 (1H, d, 2.7 Hz), 7.27 (1H, dd, 8.8, 2.7 Hz), 7.01 (1H, d, 8.8Hz), 6.64 (1H, d, 1.5 Hz), 6.45 (1H, dd, 8.2, 1.5 Hz), 4.79 (1H, d, 17.2Hz), 4.59-4.49 (1H, m), 4.53 (1H, d, 17.2 Hz), 3.92-3.84 (1H, m), 3.79(3H, s), 3.14 (1H, t, 12.8 Hz), 3.00 (1H, dd, 17.0, 12.8 Hz), 2.98 (1H,dd, 14.4, 4.6 Hz), 2.65 (1H, dd, 14.4, 9.2 Hz), 1.79-1.67 (2H, m), 0.83(3H, t, 7.2 Hz)

MS: 503 (M+H)⁺

Melting point: 139-140° C.

Example 179C2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid monoacetic acid solvate (compound 179B)

The compound 150 (121 mg) was dissolved in acetone (1.2 ml) andconcentrated. The obtained amorphous was dissolved in acetic acid (2.4ml). This solution was stirred under ice cooling for 3 hours, then theappeared precipitated crystal was collected by filtration to obtain thetitle compound (98 mg).

NMR (DMSO-d₆): δ9.41 (1H, d, J=7.7 Hz), 7.70-7.64 (2H, m), 7.33 (1H, d,J=2.7 Hz), 7.27 (1H, dd, J=8.8, 2.7 Hz), 7.01 (1H, d, J=8.7 Hz), 6.63(1H, s), 6.44 (1H, d, J=8.7 Hz), 4.78 (1H, d, J=17.4 Hz), 4.61-4.51 (2H,m), 3.94-3.82 (1H, m), 3.79 (3H, s), 3.13 (1H, t, J=12.3 Hz), 3.05-2.95(2H, m), 2.71-2.65 (1H, m), 1.9 (3H, s), 1.79-1.65 (2H, m), 0.83 (3H, t,J=7.2 Hz)

MS: 503 (M+H)⁺

Melting point: 147-149° C.

Example 180A3-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 91)

A mixed solution of the compound S163 (3.1 g) and 1N hydrochloricacid/acetic acid solution (20 ml) was stirred at room temperature for 2hours. The reaction solution was concentrated, hexane/ethylacetate/toluene was added to the residue, the mixture was stirred atroom temperature, and the precipitated solid was collected by filtrationto obtain the title compound (3.02 g).

NMR (DMSO-d₆): δ13.01 (1H, br), 9.48 (1H, d, J=7.3 Hz), 7.86 (1H, s),7.82 (1H, d, J=7.7 Hz), 7.67 (1H, d, J=3.5 Hz), 7.55 (1H, d, J=7.7 Hz),7.46 (1H, t, J=7.7 Hz), 7.33 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.8, 2.6Hz), 7.00 (1H, d, J=8.8 Hz), 4.79-4.69 (2H, m), 4.49 (1H, d, J=17.2 Hz),3.91-3.81 (1H, m), 3.79 (3H, s), 3.16 (1H, t, J=12.6 Hz), 3.05-2.96 (2H,m), 2.67 (1H, dd, J=14.3, 9.3 Hz), 1.89-1.74 (2H, m), 0.84 (3H, t, J=7.3Hz)

MS: 488 (M+H)⁺

Melting point: 121-123° C.

Example 180B sodium3-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound 180)

To sodium 2-ethylhexanoate (340 mg) in acetone (10 ml) solution, thecompound 91 (1 g) in acetone (15 ml) solution was added dropwise. Theprecipitated solid was collected by filtration and washed with ethylacetate to obtain the title compound (437 mg).

NMR (DMSO-d₆): δ9.49 (1H, d, J=7.6 Hz), 7.76 (1H, s), 7.75-7.66 (2H, m),7.33 (1H, d, J=2.7 Hz), 7.26 (1H, dd, J=8.7, 2.7 Hz), 7.25-7.15 (2H, m),7 (1H, d, J=8.7 Hz), 4.77 (1H, d, J=17.2 Hz), 4.67 (1H, q, J=7.6 Hz),4.48 (1H, d, J=17.2 Hz), 3.92-3.82 (1H, m), 3.78 (3H, s), 3.16 (1H, t,J=12.9 Hz), 3.05-2.94 (2H, m), 2.67 (1H, dd, J=14.3, 9.5 Hz), 1.88-1.70(2H, m), 0.82 (3H, t, J=7.3 Hz)

MS: 488 (M+H)⁺

Melting point: 161-163° C.

Reference Example 166 tert-butyl(2R)-2-{[(4-chlorophenyl)sulfonyl]amino}propanoate (compound S166)

To D-alanine tert-butyl ester hydrochloride (1 g) in methylene chloride(35 ml) solution, triethylamine (1.7 ml) and 4-chlorobenzenesulfonylchloride (1.1 g) were added under ice cooling and the mixture wasstirred at room temperature for 2 hours. The methylene chloride wasdistilled off in vacuo, then the residue was diluted with ethyl acetate.The obtained solution was successively washed with distilled water,saturated potassium hydrogensulfate aqueous solution, and saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated. Theresidue was recrystallized from ethyl acetate/hexane to obtain the titlecompound (1.47 g).

NMR (CDCl₃): δ7.78 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz), 5.25 (1H,brd, J=8.5 Hz), 3.90-3.81 (1H, m), 1.36 (3H, d, J=7.2 Hz), 1.30 (9H, s)

Instead of the starting material compound of Reference Example 166, thatis, D-alanine tert-butyl ester hydrochloride, the amino acid derivativesshown in Table XI were used for the similar procedure as in ReferenceExample 166 to obtain the compounds of Reference Examples 167 to 171.Note that the amino acid derivatives shown in Table XI are commerciallyavailable compounds or compounds obtained by derivation fromcommercially available compounds by known methods.

TABLE XI Amino acid Ref. Ex. derivative used as no. material Ref. Ex.167

Ref. Ex. 168

Ref. Ex. 169

Ref. Ex. 170

Ref. Ex. 171

Reference Example 167 tert-butyl(2S)-2-{[(4-chlorophenyl)sulfonyl]amino}propanoate (compound S167)

NMR (CDCl₃): δ7.78 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz), 5.25 (1H,brd, J=8.5 Hz), 3.90-3.81 (1H, m), 1.36 (3H, d, J=7.2 Hz), 1.30 (9H, s)

Reference Example 168 5-benzyl 1-tert-butyl(2R)-2-{[(4-chlorophenyl)sulfonyl]amino}pentanedioate (compound S168)

NMR (CDCl₃): δ7.75 (2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 7.43-7.31(5H, m), 5.22 (1H, brd, J=9.2 Hz), 5.13 (2H, s), 3.88-3.80 (1H, m),2.60-2.47 (2H, m), 2.19-2.09 (1H, m), 1.90-1.79 (1H, m), 1.56 (9H, s)

Reference Example 169 tert-butyl1-{[(4-chlorophenyl)sulfonyl]amino}cyclopropanecarboxylate (compoundS169)

NMR (CDCl₃): δ7.82 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz), 5.52 (1H,s), 1.50-1.47 (2H, m), 1.37-1.32 (2H, m), 1.21 (9H, s)

Reference Example 170 4-benzyl 1-tert-butyl(2R)-2-{[(4-chlorophenyl)sulfonyl]amino}succinate (compound S170)Reference Example 171 tert-butyl2-{[(4-chlorophenyl)sulfonyl]amino}3-methoxypropanoate (compound S171)Reference Example 172 tert-butyl(2R)-2-{[(4-chloro-2-nitrophenyl)sulfonyl]amino}butanoate (compoundS172)

Instead of the starting material compound of Reference Example 166, thatis, L-alanine tert-butyl ester hydrochloride, D-2-amino-n-butyric acidtert-butyl ester hydrochloride was used, further, instead of4-chlorobenzenesulfonyl chloride, 4-chloro-2-nitrobenzenesulfonylchloride was used for the similar procedure as with Reference Example167 to obtain the title compound.

NMR (CDCl₃): δ8.32 (1H, d, J=2.1 Hz), 7.97 (1H, dd, J=8.4, 2.1 Hz), 7.70(1H, d, J=8.4 Hz), 5.28 (1H, brd, J=9.2 Hz), 3.85-3.78 (1H, m),1.89-1.78 (1H, m), 1.75-1.65 (1H, m), 1.30 (9H, s), 0.95 (3H, t, J=7.5Hz)

Example 181 benzyl3-{(2R,6E)-6-(5-chloro-2-methoxybenzylidene)-1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-2-yl}propanoate(compound 181)

To the compound S23 (760 mg) in tetrahydrofuran (8 ml) solution,triethylamine (0.31 ml) and 2,4,6-trichlorobenzoyl chloride (0.35 ml)were added and the mixture was stirred at room temperature for 30minutes. The reaction solution was concentrated, then benzene (8 ml) wasadded to the residue. To the obtained solution, 4-dimethylaminopyridine(275 mg) and the compound S168 (800 mg) were added and the mixture wasstirred under heating and reflux for 1 hour. The reaction solution wasdiluted with ethyl acetate and successively washed with saturatedpotassium hydrogensulfate aqueous solution and saturated saline. Theorganic layer was dried over with anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (hexane/chloroform/ethyl acetate=8/8/1 to 7/7/1). To thepurified product, a 1M hydrogen chloride/acetic acid solution (5 ml) wasadded, the mixture was stirred at room temperature for 14 hours, thenthe reaction solution was concentrated.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg) wasadded to the residue in methylene chloride (14 ml) solution, and themixture was stirred at room temperature for 1 minute. Next,triethylamine (0.1 ml) was added to the reaction solution and themixture was stirred at room temperature for 1 hour. The reactionsolution was diluted with ethyl acetate, then was successively washedwith distilled water, saturated potassium hydrogensulfate aqueoussolution, and saturated saline. The organic layer was dried over withanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/1) to obtainthe title compound (117 mg).

NMR (CDCl₃): δ8.10 (2H, d, J=8.6 Hz), 7.67 (1H, s), 7.51 (2H, d, J=8.6Hz), 7.40-7.26 (6H, m), 7.16 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.9 Hz),6.10-6.03 (1H, br), 5.16-5.08 (1H, m), 5.10 (2H, s), 4.17-4.03 (2H, m),3.80 (3H, s), 2.49-2.33 (2H, m), 2.30-2.20 (1H, m), 2.03-1.91 (1H, m)

MS: (M+H)⁺

Example 182(3R,6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1,4-diazepan-2,5-dione(compound 182)

Instead of the starting material of Example 181, that is, the compoundS168, the compound S166 was used for the similar procedure as in Example181 to obtain the title compound.

NMR (CDCl₃): δ8.10 (2H, d, J=8.7 Hz), 7.74 (1H, s), 7.55 (2H, d, J=8.7Hz), 7.34 (1H, dd, J=8.8, 2.5 Hz), 7.15 (1H, d, J=2.5 Hz), 6.86 (1H, d,J=8.8 Hz), 6.26 (1H, brd, J=6.4 Hz), 5.12 (1H, q, J=7.6 Hz), 4.22 (1H,d, J=14.3 Hz), 4.02 (1H, dd, J=14.3, 6.4 Hz), 3.82 (3H, s), 1.36 (3H, d,J=7.6 Hz)

MS: 469 (M+H)⁺

Example 183(3S,6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1,4-diazepan-2,5-dione(compound 183)

Instead of the starting material of Example 181, that is, the compoundS168, the compound S167 was used for the similar procedure as in Example181 to obtain the title compound.

NMR (CDCl₃): δ8.12 (2H, d, J=8.8 Hz), 7.75 (1H, s), 7.57 (2H, d, J=8.8Hz), 7.36 (1H, dd, J=8.8, 2.6 Hz), 7.16 (1H, d, J=2.6 Hz), 6.87 (1H, d,J=8.8 Hz), 6.24 (1H, brd, J=6.5 Hz), 5.13 (1H, q, J=7.6 Hz), 4.24 (1H,d, J=14.1 Hz), 4.03 (1H, dd, J=14.1, 6.5 Hz), 3.83 (3H, s), 1.38 (3H, d,J=7.6 Hz)

MS: 469 (M+H)⁺

Example 184(6E)-6-(5-chloro-2-methoxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-4,8-diaspiro[2.6]nonane-5,9-dione(compound 184)

Instead of the starting material of Example 181, that is, the compoundS168, the compound S169 was used for the similar procedure as in Example181 to obtain the title compound.

NMR (CDCl₃): δ8.08 (2H, d, J=8.7 Hz), 7.533 (2H, d, J=8.7 Hz), 7.532(1H, s), 7.33 (1H, dd, J=8.9, 2.5 Hz), 7.15 (1H, d, J=2.5 Hz), 6.86 (1H,d, J=8.9 Hz), 5.87 (1H, br), 4.20 (2H, d, J=3.1 Hz), 3.83 (3H, s),2.05-1.35 (2H, m), 1.30-1.08 (2H, m)

MS: 481 (M+H)⁺

Example 185benzyl[(2R,6E)-1-[(4-chlorophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzylidene)-3,7-dioxo-1,4-diazepan-2-yl]acetate(compound 185)

The compound S177 was used instead of the starting material of Example181, that is, the compound S23, and the compound S170 was used insteadof the compound S168 for the similar procedure as in Example 181 toobtain the title compound.

NMR (CDCl₃): δ8.09 (2H, d, J=8.7 Hz), 7.67 (1H, s), 7.45 (2H, d, J=8.7Hz), 7.40-7.32 (3H, m), 7.32-7.23 (2H, m), 7.12-7.04 (1H, m), 6.91-6.82(2H, m), 6.22-6.17 (1H, br), 5.56 (1H, t, J=7.0 Hz), 5.01 (1H, d, J=14.2Hz), 4.93 (1H, d, J=14.2 Hz), 4.21 (1H, d, J=14.5 Hz), 4.04 (1H, dd,J=13.6, 6.0 Hz), 3.79 (3H, s), 2.97 (1H, dd, J=15.8, 7.2 Hz), 2.68 (1H,dd, J=15.8, 7.0 Hz)

MS: (M+H)⁺

Example 186(3R,6E)-4-[(4-chloro-3-nitrophenyl)sulfonyl]-3-ethyl-6-(5-fluoro-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 186)

Instead of the starting material of Example 185, that is, the compoundS170, the compound S172 was used for the similar procedure as in Example185 to obtain the title compound.

NMR (CDCl₃): δ8.65 (1H, d, J=2.1 Hz), 8.27 (1H, dd, J=8.5, 2.1 Hz), 7.77(1H, d, J=8.5 Hz), 7.76 (1H, s), 7.15-7.09 (1H, m), 6.97-7.85 (2H, m),6.58-6.50 (1H, br), 4.87 (1H, dd, J=9.9, 6.4 Hz), 4.21-4.07 (2H, m),3.80 (3H, s), 2.13-2.00 (1H, m), 1.87-1.71 (1H, m), 0.89 (3H, t, J=6.6Hz)

MS: (M+H)⁺

Example 187(6E)-6-(5-fluoro-2-methoxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-3-(methoxymethyl)-1,4-diazepan-2,5-dione(compound 187)

Instead of the starting material of Example 181, that is, the compoundS168, the compound S171 was used for the similar procedure as in Example181 to obtain the title compound.

NMR (CDCl₃): δ8.13 (2H, d, J=8.7 Hz), 7.73 (1H, s), 7.54 (2H, d, J=8.7Hz), 7.35 (1H, dd, J=8.8, 2.6 Hz), 7.14 (1H, d, J=2.6 Hz), 6.87 (1H, d,J=8.8 Hz), 6.43-6.36 (1H, br), 5.26-5.20 (1H, m), 4.27 (1H, dd, J=14.2,1.2 Hz), 4.00 (1H, dd, J=14.2, 7.0 Hz), 3.83 (3H, s), 3.79 (1H, dd,J=10.1, 6.3 Hz), 3.39 (1H, dd, J=10.1, 3.8 Hz), 3.00 (3H, s)

MS: 499 (M+H)⁺

Example 1883-{(2R,6S)-6-(5-chloro-2-methoxybenzyl)-1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-2-yl}propanoicacid (compound 188)

To a solution of the compound 181 (105 mg) in tetrahydrofuran (3 ml),10% platinum carbon (sulfur poisoned catalyst) (100 mg) was added andthe mixture was stirred under hydrogen atmosphere at room temperaturefor 18 hours. Next, the catalyst was filtered out, and the filtrate wasconcentrated. The residue was diluted with chloroform/hexane and theprecipitate was collected by filtration to obtain the title compound (43mg).

NMR (CDCl₃): δ7.95 (2H, d, J=8.6 Hz), 7.90 (1H, br), 7.50 (2H, d, J=8.6Hz), 7.19 (1H, dd, J=8.8, 2.5 Hz), 7.08 (1H, d, J=2.5 Hz), 6.78 (1H, d,J=8.8 Hz), 5.03 (1H, dd, J=11.2, 6.2 Hz), 3.77 (3H, s), 3.67-3.57 (1H,m), 3.25-3.12 (2H, m), 2.98-2.88 (2H, m), 2.59-2.50 (2H, m), 2.30-2.12(1H, m), 2.10-2.00 (1H, m)

MS: 529 (M+H)⁺

Example 189(2R,6S)-1-[(4-chlorophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-2-yl}aceticacid (compound 189)

Instead of the starting material of Example 188, that is, the compound181, the compound 185 was used for the similar procedure as in Example188 to obtain the title compound.

NMR (DMSO-d₆): δ12.36 (1H, br), 7.97 (2H, d, J=8.7 Hz), 7.82 (1H, br),7.73 (2H, d, J=8.7 Hz), 7.25-6.95 (3H, m), 5.33-5.30 (1H, m), 3.87-3.75(1H, m), 3.76 (3H, s), 3.22 (1H, dd, J=17.1, 8.0 Hz), 3.12-3.07 (2H, m),2.98 (1H, dd, J=14.2, 4.6 Hz), 2.73 (1H, dd, J=17.1, 5.3 Hz), 2.60-2.50(1H, m)

MS: 499 (M+H)⁺

Example 190(3R,6S)-4-[(3-amino-4-chlorophenyl)sulfonyl]-3-ethyl-6-(5-fluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 190)

Instead of the starting material of Example 188, that is, the compound181, the compound 186 was used for the similar procedure as in Example188 to obtain the title compound.

NMR (CDCl₃): δ7.42 (1H, d, J=2.1 Hz), 7.37 (1H, d, J=8.4 Hz), 7.28 (1H,dd, J=8.4, 2.1 Hz), 6.95-6.90 (1H, m), 6.84 (1H, dd, J=8.7, 3.1 Hz),6.79 (1H, dd, J=9.0, 4.4 Hz), 5.92 (1H, br), 4.98 (1H, t, J=7.6 Hz),4.35 (2H, br), 3.80 (3H, s), 3.48 (1H, ddd, J=15.7, 10.9, 4.8 Hz), 3.25(1H, dd, J=13.5, 4.7 Hz), 3.22-3.14 (1H, m), 3.12-3.02 (1H, m), 2.88(1H, dd, J=13.5, 8.6 Hz), 2.01-1.90 (2H, m), 1.01 (3H, t, J=7.4 Hz)

MS: 484 (M+H)⁺

Example 191rel-(3R,6S)-6-(5-chloro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-3-(methoxymethyl)-1,4-diazepan-2,5-dione(compound 191)

Instead of the starting material of Example 188, that is, the compound181, the compound 187 was used for the similar procedure as in Example188 to obtain the title compound.

NMR (CDCl₃): δ8.08 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz), 7.19 (1H,dd, J=8.8, 2.6 Hz), 7.09 (1H, d, J=2.6 Hz), 6.79 (1H, d, J=8.8 Hz), 6.03(1H, br), 5.12 (1H, t, J=3.7 Hz), 4.02 (1H, dd, J=9.7, 3.7 Hz), 3.83(3H, s), 3.80-3.75 (1H, m), 3.72-3.68 (1H, m), 3.38-3.28 (1H, m),3.22-3.17 (1H, m), 3.10 (3H, s), 3.02-2.92 (2H, m)

MS: 501 (M+H)⁺

Example 1924-[(4-chlorophenyl)sulfonyl]-6-(2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 192)

To the compound 29 (40 mg) in acetic acid (2 ml) solution, 5% palladiumcarbon (60 mg) was added and the mixture was stirred under hydrogenatmosphere at room temperature for 22 hours. Next, the catalyst wasfiltered out, and the filtrate was concentrated. The residue waspurified by preparative thin layer chromatography (diethylether) toobtain the title compound (9.1 mg).

NMR (CDCl₃): δ7.97 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.22 (1H,d, J=7.7 Hz), 7.03 (1H, d, J=7.2 Hz), 6.90-6.84 (2H, m), 5.67 (1H, br),4.98 (1H, d, J=17.6 Hz), 4.40 (1H, d, J=17.6 Hz), 3.81 (3H, s),3.54-3.42 (1H, m), 3.25-3.08 (3H, m), 2.56 (1H, dd, J=14.0, 9.1 Hz)

MS: 423 (M+H)⁺

Example 193(6E)-6-(2-hydroxy-5-methylbenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 193)

To(6E)-6-[2-(methoxymethoxy)-5-methylbenzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(95 mg), synthesized by using, instead of the starting material ofReference Example 117, that is, the compound S6, the compound Sil forthe similar procedure as in Reference Example 117, Reference Example122, and Example 1, in methylene chloride (0.48 ml) solution,trifluoroacetic acid (0.48 ml) was added and the mixture was stirred atroom temperature for 45 minutes. Next, the reaction solution wasconcentrated, and the residue was recrystallized from hexane/ethylacetate to obtain the title compound (87 mg).

NMR (CDCl₃): δ8.01 (2H, d, J=8.7 Hz), 7.71 (1H, s), 7.5 (2H, d, J=8.7Hz), 7.06 (1H, d, J=8.2 Hz), 6.86 (1H, s), 6.75 (1H, d, J=8.2 Hz), 6.01(1H, br), 4.72 (2H, s), 4.21 (2H, d, J=4.7 Hz), 2.26 (3H, s)

MS: 421 (M+H)⁺

Example 1944-[(4-chlorophenyl)sulfonyl]-6-(4-hydroxybenzyl)-1,4-diazepan-2,5-dione(compound 194)

4-[(4-chlorophenyl)sulfonyl]-6-[4-(methoxymethoxy)benzyl]-1,4-diazepan-2,5-dione,synthesized by using, instead of the starting material of ReferenceExample 124, that is, the compound S120, the compound S121 for thesimilar procedure as in Reference Example 124, Example 1, and Example29, was used instead of the starting material compound of Example 193that is,(6E)-6-[2-(methoxymethoxy)-5-methylbenzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione,for the similar procedure as in Example 193 to obtain the titlecompound.

NMR (DMSO-d₆): δ9.21 (1H, s), 7.93 (2H, d, J=8.6 Hz), 7.85 (1H, br),7.73 (2H, d, J=8.6 Hz), 6.98 (2H, d, J=8.2 Hz), 6.64 (2H, d, J=8.2 Hz),4.87 (1H, d, J=17.5 Hz), 4.52 (1H, d, J=17.5 Hz), 3.65-3.56 (1H, m),3.07-2.98 (2H, m), 2.84 (1H, dd, J=14.2, 4.5 Hz), 2.37-2.27 (1H, m)

MS: 409 (M+H)⁺

Example 195(6E)-4-[(4-chlorophenyl)sulfonyl]-6-(5-hydroxy-2-methoxybenzylidene)-1,4-diazepan-2,5-dione(compound 195)

(6E)-6-[2-methoxy-5-(methoxymethoxy)benzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione,synthesized by using, instead of the starting material of ReferenceExample 117, that is, the compound S6, the compound S22 for the similarprocedure as in Reference Example 117, Reference Example 122, andExample 1, was used instead of the starting material compound of Example193, that is,(6E)-6-[2-(methoxymethoxy)-5-methylbenzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione,for the similar procedure as in Example 193 to obtain the titlecompound.

NMR (CDCl₃): δ8.04 (2H, d, J=8.6 Hz), 7.79 (1H, s), 7.52 (2H, d, J=8.6Hz), 7.08 (1H, br), 6.89 (1H, dd, J=8.9, 2.9 Hz), 6.80 (1H, d, J=8.9Hz), 6.73 (1H, d, J=2.9 Hz), 4.61 (2H, s), 4.23 (2H, d, J=4.3 Hz), 3.76(3H, s)

MS: 437 (M+H)⁺

Example 196([2-chloro-5-{[(6E)-6-(5-chloro-2-methoxybenzylidene)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoicacid (compound 196)

Instead of the starting material compound of Reference Example 117, thatis, 4-chlorobenzenesulfonamide, the compound S56 was used for thesimilar procedure as in Reference Example 117, Reference Example 122,Example 1, and Example 251 to obtain the title compound.

NMR (DMSO-d₆): δ14.00 (1H, s), 8.28 (1H, d, J=4.3 Hz), 8.06 (1H, t,J=4.9 Hz), 8.03 (1H, dd, J=8.5, 2.4 Hz), 7.85 (1H, d, J=8.5 Hz), 7.54(1H, s), 7.45 (1H, dd, J=8.9, 2.5 Hz), 7.26 (1H, d, J=2.5 Hz), 7.10 (1H,d, J=8.9 Hz), 4.71 (2H, s), 4.16 (2H, d, J=4.3 Hz), 3.79 (3H, s)

MS: 499 (M+H)⁺

Example 1972-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoicacid (compound 197)

Instead of the starting material compound of Reference Example 117, thatis 4-chlorobenzenesulfonamide, the compound S56 was used for the similarprocedure as in Reference Example 117, Reference Example 122, Example 1,Example 29, and Example 251 to obtain the title compound.

NMR (DMSO-d₆): δ13.99 (1H, brs), 8.28 (1H, d, J=2.3 Hz), 8.04 (1H, dd,J=8.5, 2.3 Hz), 7.88-7.83 (1H, m), 7.85 (1H, d, J=8.5 Hz), 7.28-7.21(2H, m), 6.97 (1H, d, J=8.5 Hz), 4.88 (1H, d, J=17.5 Hz), 4.53 (1H, d,J=17.5 Hz), 3.75 (3H, s), 3.72-3.61 (1H, m), 3.03-2.99 (2H, m), 2.84(1H, dd, J=14.3, 4.8 Hz), 2.57-2.50 (1H, m)

MS: 501 (M+H)⁺

Reference Example 173 2-benzyl-3-[(benzyloxycarbonyl)amino]propanoicacid (compound S173)

To methyl(2E)-2-(azide methyl)-3-phenyl-2-propanoate (10 g), obtained byusing, instead of the starting material compound of Reference Example 2,that is, the compound S1, benzaldehyde for the similar procedure as withReference Example 2 to Reference Example 4, ethanol (200 ml), aceticacid (2.6 ml), and 10% palladium carbon (0.48 g) were added and themixture was stirred under hydrogen atmosphere at room temperature for 3hours. The reaction solution was filtered, then the concentratedfiltrate was diluted with 2N hydrochloric acid and washed with ethylacetate. The aqueous phase was basified by a 4N sodium hydroxide aqueoussolution, then tetrahydrofuran (50 ml) and benzyl chloroformate (1.2 ml)were added at 0° C. and the mixture was stirred at 0° C. for 2 hours.The organic solvent in the reaction solution was distilled off, then theobtained aqueous mixture was extracted with ethyl acetate. The extractwas successively washed with water and saturated saline, was dried overwith sodium sulfate, then was concentrated. The obtained residue waspurified by silica gel column chromatography (hexane-ethyl acetate=7:1)to obtain methyl 2-benzyl-3-[(benzyloxycarbonyl)amino]propanoate (7.9 g,including benzyl alcohol). Ethanol (60 ml) and 2N sodium hydroxideaqueous solution (15 ml) were added to this, then the mixture wasstirred at room temperature for 2 hours. The organic solvent in thereaction solution was distilled off, water (20 ml) was added, themixture was washed with ethyl acetate, then the obtained aqueous phasewas acidified by a 10% potassium hydrogensulfate aqueous solution andextracted with diethylether. The extract was successively washed withwater and saturated saline, dried over with anhydrous sodium sulfate,and concentrated to obtain the title compound.

Example 198 3-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzoicacid (compound 198)

Instead of the starting material compound of Reference Example 117, thatis, the compound S6, the compound S173 was used, and instead of4-chlorobenzenesulfonamide, 3-(tert-butoxycarbonyl)benzenesulfonamidewas used, for the similar procedure as with Reference Example 117 toobtain tert-butyl3-{[(2-benzyl-3-benzyloxycarbonylamino)propanoyl]aminosulfonyl}benzoate(1.95 g). To this, ethanol (20 ml) and 20% palladium hydroxide on carbon(0.22 g) were added and the mixture was stirred under hydrogenatmosphere at room temperature for 17 hours. The reaction solution wasfiltered, and the filtrate was concentrated to obtain tert butyl4-{[(3-amino-2-benzylpropanoyl)amino]sulfonyl}benzoate. This was usedinstead of the starting material of Reference Example 124, that is, thecompound S120, for the similar procedure as with Reference Example 124,Example 1, and Example 251 to obtain the title compound.

NMR (DMSO-d₆): δ13.72-13.42 (1H, br), 8.42 (1H, s), 8.27 (1H, d, J=7.8Hz), 8.15 (1H, d, J=7.8 Hz), 7.86 (1H, br), 7.79 (1H, t, J=7.8 Hz),7.29-7.12 (5H, m), 4.92 (1H, d, J=17.4 Hz), 4.55 (1H, d, J=17.4 Hz),3.79-3.69 (1H, m), 3.08-2.91 (3H, m), 2.50-2.41 (1H, m)

MS: 403 (M+H)⁺

Example 1992-amino-4-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoicacid (compound 199)

Instead of the starting material of Example 178, that is, the compoundS164, the compound 50 was used for the similar procedure as in Example178 to obtain the title compound.

NMR (DMSO-d₆): δ7.88-7.85 (1H, m), 7.86 (1H, d, 8.4 Hz), 7.41 (1H, d,1.9 Hz), 7.29-7.24 (2H, m), 6.98 (1H, d, 9.6 Hz), 6.88 (1H, dd, 8.4, 1.9Hz), 4.88 (1H, d, 17.5 Hz), 4.48 (1H, d, 17.5 Hz), 3.75 (3H, s),3.72-3.64 (1H, m), 3.04-2.99 (2H, m), 2.85 (1H, dd, 14.5, 4.9 Hz),2.56-2.50 (1H, m)

MS: 482 (M+H)⁺

Example 2004-[(3-amino-4-methylphenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dionehydrochloride (compound 200)

Instead of the starting material of Example 178, that is, the compoundS164, the compound S2 was used for the similar procedure as in Example178 to obtain the title compound.

NMR (DMSO-d₆): δ7.81 (1H, br), 7.29 (1H, s), 7.26-7.23 (2H, m), 7.19(1H, d, 8.0 Hz), 7.03 (1H, d, 8.0 Hz), 6.97 (1H, d, 9.5 Hz), 4.83 (1H,d, 17.4 Hz), 4.48 (1H, d, 17.4 Hz), 3.75 (3H, s), 3.69-3.60 (1H, m),3.00-2.96 (2H, m), 2.83 (1H, dd, 14.3, 4.6 Hz), 2.56-2.49 (1H, m), 2.15(3H, s)

MS: 452 (M+H)⁺

Example 2014-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-2-hydroxybenzoicacid (compound 201)

Instead of the starting material compound of Reference Example 117, thatis, 4-chlorobenzenesulfonamide, tert-butyl4-aminosulfonyl-2-hydroxybenzoate was used for the similar procedure asin Reference Example 117, Reference Example 122, Example 1, Example 29,and Example 178 to obtain the title compound.

NMR (DMSO-d₆): δ7.96 (1H, d, 8.2 Hz), 7.87 (1H, br), 7.41-7.37 (2H, m),7.28-7.21 (2H, m), 6.97 (1H, d, 8.5 Hz), 4.91 (1H, d, 17.5 Hz), 4.52(1H, d, 17.5 Hz), 3.75 (3H, s), 3.72-3.63 (1H, m), 3.04-2.99 (2H, m),2.84 (1H, dd, 14.3, 4.9 Hz), 2.56-2.48 (1H, m), 2.30 (3H, s), 2.11 (9H,s)

MS: 483 (M+H)⁺

Example 2024-[(4-amino-5-chloro-2-thienyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 202)

Instead of the starting material compound of Reference Example 117, thatis, 4-chlorobenzenesulfonamide, the compound S64 was used for thesimilar procedure as in Reference Example 117, Reference Example 122,Example 1, Example 29, and Example 178 to obtain the title compound.

NMR (CDCl₃): δ7.37 (1H, s), 7.20 (1H, dd, J=8.8, 2.6 Hz), 7.07 (1H, d,J=2.6 Hz), 6.79 (1H, d, J=8.8 Hz), 5.74 (1H, br), 4.89 (1H, d, J=17.8Hz), 4.34 (1H, d, J=17.8 Hz), 3.82 (2H, s), 3.81 (3H, s), 3.51-3.41 (1H,m), 3.33-3.24 (2H, m), 3.19 (1H, dd, J=14.1, 4.7 Hz), 2.59 (1H, dd,J=14.1, 9.1 Hz)

MS: 478 (M+H)⁺

Example 2034-{[4-(2-aminoethyl)phenyl]sulfonyl}-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dionehydrochloride (compound 203)

Instead of the starting material of Example 178, that is, the compoundS164, the compound 62 was used for the similar procedure as in Example178 to obtain the title compound.

NMR (DMSO-d₆): δ7.95 (3H, br), 7.88 (2H, d, 8.3 Hz), 7.84 (1H, br), 7.54(2H, d, 8.3 Hz), 7.27-7.22 (2H, m), 6.97 (1H, d, 8.6 Hz), 4.87 (1H, d,17.5 Hz), 4.55 (1H, d, 17.5 Hz), 3.74 (3H, s), 3.72-3.64 (1H, m),3.13-3.06 (2H, m), 3.01-2.96 (4H, m), 2.82 (1H, d, 14.3, 4.8 Hz),2.57-2.49 (1H, m)

MS: 466 (M+H)⁺

Example 204(6E)-6-(2-amino-5-chlorobenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 204)

To the compound 5 (77 mg) in 1,4-dioxane (1.5 ml) solution, acetic acid(0.77 ml) and iron reduced (46 mg) were added at room temperature andthe mixture was stirred at 100° C. for 3 hours. Ethyl acetate anddistilled water were added to the reaction solution and the mixtureseparated. The organic layer was dried by anhydrous sodium sulfate, thenconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1), then the obtained purifiedproduct was recrystallized from hexane/ethyl acetate to obtain the titlecompound (41 mg).

NMR (CDCl₃): δ8.02 (2H, d, J=8.7 Hz), 7.59 (1H, s), 7.52 (2H, d, J=8.7Hz), 7.13 (1H, dd, J=8.7, 2.2 Hz), 6.90 (1H, d, J=2.2 Hz), 6.65 (1H, d,J=8.7 Hz), 5.89 (1H, br), 4.74 (2H, s), 4.24 (2H, d, J=5.0 Hz), 3.77(2H, brs)

MS: 440 (M+H)⁺

Example 2054-[(4-aminophenyl)sulfonyl]-6-(3-chlorobenzyl)-1,4-diazepan-2,5-dione(compound 205)

To the compound 173 (14 mg) in methanol (1.4 ml) solution, platinumoxide (4.2 mg) was added and the mixture was stirred under hydrogenatmosphere at room temperature for 1 hour. The insoluble compound wasfiltered out, then the filtrate was concentrated. Hexane/ethyl acetatewas added to the residue, then the precipitate was collected byfiltration to obtain the title compound (9.4 mg).

NMR (DMSO-d₆): δ7.76 (1H, br), 7.51 (2H, d, J=8.7 Hz), 7.35 (1H, s),7.31-7.17 (3H, m), 6.59 (2H, d, J=8.7 Hz), 6.25 (2H, brs), 4.82 (1H, d,J=17.5 Hz), 4.49 (1H, d, J=17.5 Hz), 3.79-3.69 (1H, m), 3.01-2.83 (3H,m), 2.57-2.42 (1H, m)

MS: 408 (M+H)⁺

Example 206tert-butyl[4-chloro-2-((E)-{1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-6-ylidene}methyl)phenoxy]acetate(compound 206)

To(6E)-6-(5-chloro-2-hydroxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(364 mg), synthesized from the compound S21 and4-chlorobenzenesulfonamide by the similar procedure as with ReferenceExample 117, Reference Example 122, Example 1, and Example 193, inN,N-dimethylformamide (7.3 ml) solution, sodium hydrogencarbonate (89mg), sodium iodide (12 mg), and tert-butyl bromoacetate (0.19 ml) wereadded and the mixture was stirred at room temperature for 17 hours. Thereaction solution was diluted with ethyl acetate, then the obtainedsolution was successively washed with saturated ammonium chlorideaqueous solution and saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/1), then the obtainedpurified product was recrystallized from hexane/ethyl acetate to obtainthe title compound (247 mg).

NMR (CDCl₃): δ8.03 (2H, d, J=8.7 Hz), 7.60 (1H, s), 7.51 (2H, d, J=8.7Hz), 7.29-7.26 (1H, m), 7.09 (1H, d, J=2.4 Hz), 6.70 (1H, d, J=8.9 Hz),6.18-6.12 (1H, br), 4.76 (2H, s), 4.50 (2H, s), 4.18 (2H, dd, J=4.8, 0.9Hz), 1.59 (5H, s), 1.48 (4H, s)

MS: 499 (M-tBu)⁺

Example 207 tert-butyl{6-benzyl-4-[(4-chlorophenyl)sulfonyl]-2,5-dioxo-1,4-diazepan-1-yl}acetate(compound 207)

To the compound 177 (50 mg) in N,N-dimethylformamide (0.5 ml) solution,tert-butyl bromoacetate (0.04 ml) and sodium hydride (60% mineral oildispersion) (12 mg) were added under ice cooling and the mixture wasstirred at room temperature for 1 hour. Saturated ammonium chlorideaqueous solution and distilled water were added to the reactionsolution, then the mixture was extracted with ethyl acetate. The organiclayer was successively washed with saturated saline, dried over withanhydrous sodium sulfate, then concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=2/1), then thepurified product was recrystallized from hexane/ethyl acetate to obtainthe title compound (10 mg).

NMR (CDCl₃): δ7.97 (2H, d, J=8.6 Hz), 7.50 (2H, d, J=8.6 Hz), 7.33-7.20(3H, m), 7.13 (2H, d, J=7.1 Hz), 4.99 (1H, d, J=17.6 Hz), 4.55 (1H, d,J=17.6 Hz), 3.86 (1H, d, J=17.1 Hz), 3.80 (1H, d, J=17.1 Hz), 3.53-3.43(1H, m), 3.31 (1H, t, J=11.9 Hz), 3.27-3.16 (2H, m), 2.58 (1H, dd,J=14.4, 8.3 Hz), 1.39 (9H, s)

MS: 529 (M+Na)⁺

Example 208 methyl2-chloro-5-{[(6E)-6-(5-chloro-2-methoxybenzylidene)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoate(compound 208)

To the compound 196 (40.6 mg) in ethyl acetate/methanol=3/1 (3 ml)solution, trimethylsilyldiazomethane (10% hexane solution) (0.5 ml) wasadded and the mixture was stirred at room temperature for 10 minutes.The reaction solution was concentrated, then residue was recrystallizedfrom methylene chloride/hexane to obtain the title compound (15.4 mg).

NMR (CDCl₃): δ8.53 (1H, d, J=2.4 Hz), 8.10 (1H, dd, J=8.6, 2.4 Hz), 7.68(1H, s), 7.63 (1H, d, J=8.6 Hz), 7.32 (1H, dd, J=8.9, 2.4 Hz), 7.05 (1H,d, J=2.4 Hz), 6.85 (1H, d, J=8.9 Hz), 5.97 (1H, br), 4.70 (2H, s), 4.215(1H, d, J=4.6 Hz), 4.212 (1H, d, J=4.5 Hz), 3.97 (3H, s), 3.81 (3H, s)

MS: 513 (M+H)⁺

Example 209 methylrel-(1R,6S)-3-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound 209)

Instead of the starting material of Reference Example 142A, that is, thecompound S83, the compound S87 was used for the similar procedure aswith Reference Example 142A, Example 91, and Example 208 to obtain thetitle compound.

NMR (CDCl₃): δ9.49 (1H, d, J=7.5 Hz), 7.96 (1H, s), 7.92 (1H, d, J=7.7Hz), 7.49 (1H, d, J=7.7 Hz), 7.40 (1H, t, J=7.7 Hz), 7.20 (1H, dd,J=8.7, 2.5 Hz), 7.11 (1H, d, J=2.5 Hz), 6.79 (1H, d, J=8.7 Hz), 5.75(1H, br), 5.35 (1H, d, J=17.6 Hz), 4.82 (1H, q, J=7.5 Hz), 4.10 (1H, d,J=17.6 Hz), 3.91 (3H, s), 3.82 (3H, s), 3.72-3.61 (1H, m), 3.31-3.27(2H, m), 3.18 (1H, dd, J=13.9, 5.1 Hz), 2.60 (1H, dd, J=13.9, 8.3 Hz),1.94-1.79 (2H, m), 0.90 (3H, t, J=7.3 Hz)

MS: 502 (M+H)⁺

Example 210 methyl3-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzoate (compound210)

Instead of the starting material of Example 208, that is, the compound196, the compound 198 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (DMSO-d₆): δ8.43 (1H, s), 8.29 (1H, d, J=8 Hz), 8.18 (1H, d, J=8.0Hz), 7.85 (1H, br), 7.82 (1H, t, J=8.0 Hz), 7.30-7.14 (5H, m), 4.92 (1H,d, J=17.5 Hz), 4.56 (1H, d, J=17.5 Hz), 3.92 (3H, s), 3.78-3.67 (1H, m),3.08-2.91 (3H, m), 2.44 (1H, dd, J=14.2, 9.0 Hz)

MS: 417 (M+H)⁺

Example 211 methyl4-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzoate (compound211)

4-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzoic acid,synthesized by using 4-(tert-butoxycarbonyl)benzenesulfonamide insteadof the starting material compound of Example 198, that is,3-(tert-butoxycarbonyl)benzenesulfonamide for the similar procedure asin Example 198, was used instead of the starting material of Example208, that is, the compound 196, for the similar procedure as withExample 208 to obtain the title compound.

NMR (DMSO-d₆): δ8.17 (2H, d, J=8.3 Hz), 8.06 (2H, d, J=8.3 Hz), 7.86(1H, br), 7.29-7.17 (5H, m), 4.93 (1H, d, J=17.5 Hz), 4.55 (1H, d,J=17.5 Hz), 3.91 (3H, s), 3.79-3.68 (1H, m), 3.08-2.90 (3H, m),2.54-2.39 (1H, m)

MS: 417 (M+H)⁺

Example 212 methyl2-amino-4-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoate(compound 212)

Instead of the starting material of Example 208, that is, the compound196, the compound 199 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (DMSO-d₆): δ7.87 (1H, d, 8.6 Hz), 7.85 (1H, m), 7.45 (1H, d, 1.4Hz), 7.26-7.23 (2H, m), 7.08 (2H, s), 6.97 (1H, d, 9.3 Hz), 6.86 (1H,dd, 8.6, 1.4 Hz), 4.88 (1H, d, 17.5 Hz), 4.48 (1H, d, 17.5 Hz), 3.83(3H, s), 3.75 (3H, s), 3.72-3.63 (1H, m), 3.01-2.98 (2H, m), 2.84 (1H,dd, 14.3, 4.7 Hz), 2.55-2.49 (1H, m)

MS: 496 (M+H)⁺

Example 213 methyl4-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-2-hydroxybenzoate(compound 213)

Instead of the starting material of Example 208, that is, the compound196, the compound 201 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (DMSO-d₆): δ10.88 (1H, brs), 7.90 (1H, d, 8.4 Hz), 7.86 (1H, br),7.49 (1H, d, 1.7 Hz), 7.39 (1H, dd, 8.4, 1.7 Hz), 7.27-7.23 (2H, m),6.97 (1H, d, 8.4 Hz), 4.90 (1H, d, 17.5 Hz), 4.51 (1H, d, 17.5 Hz), 3.88(3H, s), 3.75 (3H, s), 3.74-3.64 (1H, m), 3.03-2.99 (2H, m), 2.84 (1H,dd, 14.2, 4.8 Hz), 2.57-2.49 (1H, m)

MS: 497 (M+H)⁺

Example 214methyl[(2R,6S)-1-[(4-chlorophenyl)sulfonyl]-6-(5-fluoro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-2-yl]acetate(compound 214)

Instead of the starting material of Example 208, that is, the compound196, the compound 189 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (CDCl₃): δ8.04 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 6.93 (1H,dt, J=8.7, 3.0 Hz), 6.87 (1H, dd, J=8.7, 3.0 Hz), 6.80 (1H, dd, J=8.7, 4Hz), 5.79 (1H, br), 5.20 (1H, dd, J=7.9, 4.9 Hz), 3.81 (3H, s),3.75-3.65 (1H, m), 3.60 (3H, s), 3.47-3.21 (4H, m), 2.87 (1H, dd,J=17.2, 4.9 Hz), 2.66 (1H, dd, J=14.0, 9.2 Hz)

MS: 513 (M+H)⁺

Melting point: 73-76° C.

Example 215 methyl3-{(2R,6S)-6-(5-chloro-2-methoxybenzyl)-1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-2-yl}propanoate(compound 215)

Instead of the starting material of Example 208, that is, the compound196, the compound 188 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (CDCl₃): δ7.99 (2H, d, J=8.6 Hz), 7.51 (2H, d, J=8.6 Hz), 7.19 (1H,dd, J=8.7, 2.4 Hz), 7.08 (1H, d, J=2.4 Hz), 6.79 (1H, d, J=8.7 Hz), 5.97(1H, br), 5.14 (1H, t, J=7.8 Hz), 3.81 (3H, s), 3.69 (3H, s), 3.48 (1H,ddd, J=15.4, 11.3, 4.4 Hz), 3.32-3.19 (2H, m), 3.11 (1H, dt, J=15.4, 5.4Hz), 2.82 (1H, dd, J=13.5, 8.6 Hz), 2.59-2.42 (2H, m), 2.39-2.28 (1H,m), 2.24-2.15 (1H, m)

MS: 543 (M+H)⁺

Example 216 methyl4-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)benzoate(compound 216)

Instead of the starting material of Example 208, that is, the compound196, the compound 168 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (CDCl₃): δ11.46 (1H, s), 8.02 (2H, d, J=8.7 Hz), 7.62 (2H, d, J=8.7Hz), 7.23 (1H, dd, J=8.7, 2.5 Hz), 7.17 (1H, d, J=2.5 Hz), 6.83 (1H, d,J=8.7 Hz), 5.76 (1H, br), 5.46 (1H, d, J=17.5 Hz), 4.22 (1H, d, J=17.5Hz), 3.91 (3H, s), 3.85 (3H, s), 3.84-3.76 (1H, m), 3.42-3.37 (2H, m),3.23 (1H, dd, J=13.9, 5.4 Hz), 2.66 (1H, dd, J=13.9, 7.9 Hz)

MS: 460 (M+H)⁺

Example 217 methyl3-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)benzoate(compound 217)

Instead of the starting material of Example 208, that is, the compound196, the compound 169 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (CDCl₃): δ11.34 (1H, s), 8.12 (1H, s), 7.84 (1H, d, J=8.0 Hz), 7.80(1H, d, J=8.0 Hz), 7.41 (1H, t, J=8.0 Hz), 7.23 (1H, dd, J=8.7, 2.6 Hz),7.17 (1H, d, J=2.6 Hz), 6.82 (1H, d, J=8.7 Hz), 5.91 (1H, br), 5.46 (1H,d, J=17.5 Hz), 4.22 (1H, d, J=17.5 Hz), 3.92 (3H, s), 3.85 (3H, s),3.84-3.36 (1H, m), 3.42-3.36 (2H, m), 3.23 (1H, dd, J=14.0, 5.5 Hz),2.66 (1H, dd, J=14.0, 8.0 Hz)

MS: 460 (M+H)⁺

Example 218 methylrel-(1R,6R)-3-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound 218)

Instead of the starting material of Reference Example 142A, that is, thecompound S83, the compound S87 was used for the similar procedure as inReference Example 142A, Example 91, and Example 208 to obtain the titlecompound.

NMR (CDCl₃): δ9.50 (1H, d, J=7.4 Hz), 7.95 (1H, s), 7.91 (1H, d, J=7.6Hz), 7.47 (1H, d, J=7.6 Hz), 7.39 (1H, t, J=7.6 Hz), 7.20 (1H, dd,J=8.7, 2.6 Hz), 7.11 (1H, d, J=2.6 Hz), 6.79 (1H, d, J=8.7 Hz), 5.70(1H, br), 5.32 (1H, d, J=17.3 Hz), 4.80 (1H, q, J=7.4 Hz), 4.06 (1H, d,J=17.3 Hz), 3.90 (3H, s), 3.82 (3H, s), 3.72-3.62 (1H, m), 3.34-3.29(2H, m), 3.19 (1H, dd, J=13.9, 5.0 Hz), 2.60 (1H, dd, J=13.9, 8.6 Hz),1.95-1.80 (2H, m), 0.92 (3H, t, J=7.3 Hz)

MS: 502 (M+H)⁺

Example 219 methylrel-(1R,6R)-4-[1-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate(compound 219)

Instead of the starting material of Example 208, that is, the compound196, the compound 113 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (CDCl₃): δ9.52 (1H, d, J=7.3 Hz), 7.99 (2H, d, J=8.2 Hz), 7.33 (2H,d, J=8.2 Hz), 7.20 (1H, dd, J=8.7, 2.5 Hz), 7.12 (1H, d, J=2.5 Hz), 6.79(1H, d, J=8.7 Hz), 5.75 (1H, br), 5.33 (1H, d, J=17.5 Hz), 4.82 (1H, q,J=7.3 Hz), 4.06 (1H, d, J=17.5 Hz), 3.89 (3H, s), 3.81 (3H, s),3.72-3.61 (1H, m), 3.35-3.30 (2H, m), 3.18 (1H, dd, J=13.9, 5.1 Hz),2.61 (1H, dd, J=13.9, 8.4 Hz), 1.92-1.78 (2H, m), 0.91 (3H, t, J=7.4 Hz)

MS: 502 (M+H)⁺

Example 220 tert-butyl{[2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}acetate(compound 220)

To the compound 119 (50 mg) in methylene chloride (3 ml) solution,glycine tert-butyl ester hydrochloride (41 mg), triethylamine (0.29 ml),and n-propyl phosphoric acid anhydride (25% ethyl acetate solution)(0.37 ml) were added and the mixture was stirred at room temperature for3 hours. The reaction solution was concentrated, then ethyl acetate wasadded to the residue. The obtained solution was successively washed withdistilled water, saturated potassium hydrogensulfate aqueous solution,saturated saline, saturated sodium hydrogencarbonate aqueous solution,and saturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. The precipitate was washed with diethylether/hexane andcollected by filtration to obtain the title compound (41.6 mg).

NMR (CDCl₃): δ9.44 (0.5H, d, 7.2 Hz), 9.40 (0.5H, d, 7.0 Hz), 7.23-7.20(1H, m), 7.14 (0.5H, d, 2.6 Hz), 7.11 (0.5H, d, 2.5 Hz), 6.81 (1H, d,8.7 Hz), 6.46 (1H, brd, 4.3 Hz), 5.76 (1H, brd, 4.3 Hz), 5.36 (0.5H, d,17.6 Hz), 5.34 (0.5H, d, 17.6 Hz), 4.36-4.27 (1H, m), 4.14 (1H, d, 17.6Hz), 3.98-3.92 (2H, m), 3.84 (1.5H, s), 3.83 (1.5H, s), 3.76-3.65 (1H,m), 3.37-3.29 (2H, m), 3.25-3.17 (1H, m), 2.67-2.57 (1H, m), 2.03-1.91(1H, m), 1.85-1.75 (1H, m), 1.47 (9H, s), 1.05-0.98 (3H, m)

MS: 469 (M+H)⁺

Example 2216-(5-chloro-2-methoxybenzyl)-4-{[4-chloro-3-(4-morpholinylcarbonyl)phenyl]sulfonyl}-1,4-diazepan-2,5-dione(compound 221)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, morpholine was used for the similar procedure as inExample 220 to obtain the title compound.

NMR (DMSO-d₆): δ8.00-7.94 (2H, m), 7.87-7.84 (2H, m), 7.26-7.19 (2H, m),6.97 (1H, d, 8.9 Hz), 4.91-4.82 (1H, m), 4.57-4.52 (1H, m), 3.80-3.43(7H, m), 3.75 (3H, s) 3.18-3.07 (2H, m), 3.04-2.98 (2H, m), 2.89-2.80(1H, m), 2.59-2.50 (1H, m)

MS: 570 (M+H)⁺

Example 2226-(5-chloro-2-methoxybenzyl)-4-{[4-chloro-3-(1-pyrrolidinylcarbonyl)phenyl]sulfonyl}-1,4-diazepan-2,5-dione(compound 222)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, pyrrolidine was used for the similar procedure asin Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ8.00-7.91 (2H, m), 7.89-7.80 (2H, m), 7.27-7.19 (2H, m),6.97 (1H, d, 8.5 Hz), 4.87 (1H, d, 17.4 Hz), 4.54 (1H, d, 17.4 Hz), 3.75(3H, s) 3.70-3.62 (1H, m), 3.52-3.47 (2H, m), 3.10-2.97 (4H, m),2.87-2.78 (1H, m), 2.62-2.50 (1H, m), 1.94-1.79 (4H, m)

MS: 554 (M+H)⁺

Example 223 tert-butyl4-(2-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzoyl)-1-piperadinecarboxylate (compound 223)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, N-(tert-butoxycarbonyl)piperadine was used for thesimilar procedure as in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ7.80-7.97 (1H, m), 7.98 (1H, d, 8.5 Hz), 7.87-7.84 (1H,m), 7.85 (1H, d, 8.5 Hz), 7.26-7.20 (2H, m), 6.97 (1H, d, 9.0 Hz), 4.87(0.5H, d, 17.2 Hz), 4.85 (0.5H, d, 17.2 Hz), 4.53 (1H, d, 17.2 Hz), 3.75(3H, s) 3.73-3.55 (3H, m), 3.50-3.39 (2H, m), 3.38-3.22 (2H, m),3.15-3.05 (2H, m), 3.04-2.95 (2H, m), 2.89-2.79 (1H, m), 2.60-2.50 (1H,m)

MS: 613 (M+H)⁺

Example 2242-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-(2-hydroxyethyl)benzamide(compound 224)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, 2-hydroxyethylamine was used for the similarprocedure as in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ8.64 (1H, t, 5.5 Hz), 7.98-7.92 (2H, m), 7.85 (1H, br),7.79 (1H, d, 8.3 Hz), 7.29-7.24 (2H, m), 6.98 (1H, d, 9.5 Hz), 4.87 (1H,d, 17.5 Hz), 4.77 (1H, t, 5.5 Hz), 4.54 (1H, d, 17.5 Hz), 3.75 (3H, s)3.70-3.63 (1H, m), 3.56-3.50 (2H, m), 3.43-3.30 (2H, m), 3.08-2.95 (2H,m), 2.85 (1H, dd, 14.3, 4.5 Hz), 2.59-2.49 (1H, m)

MS: 544 (M+H)⁺

Example 2252-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-(3-pyridylmethyl)benzamide(compound 225)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, 3-picolylamine was used for the similar procedureas in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ9.26 (1H, t, 5.9 Hz), 8.61 (1H, s), 8.51 (1H, d, 4.5Hz), 8.01-7.98 (2H, m), 7.87-7.81 (3H, m), 7.44 (1H, dd, 7.8, 4.9 Hz),7.29-7.24 (2H, m), 6.98 (1H, d, 9.5 Hz), 4.88 (1H, d, 17.7 Hz),4.58-4.52 (3H, m), 3.75 (3H, s), 3.72-3.63 (1H, m), 3.13-2.95 (2H, m),2.85 (1H, dd, 14.4, 4.6 Hz), 2.57-2.49 (1H, m)

MS: 591 (M+H)⁺

Example 2262-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-methyl-N-phenylbenzamide(compound 226)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, N-methylaniline was used for the similar procedureas in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ7.95 (1H, brs), 7.86 (1H, brs), 7.73 (1H, brd, 8.2 Hz),7.57 (1H, brd, 8.2 Hz), 7.32-7.20 (6H, m), 7.15 (1H, brs), 7.00 (1H,brd, 9.1 Hz), 4.80 (1H, d, 17.3 Hz), 4.50 (1H, d, 17.3 Hz), 3.77 (3H,s), 3.72-3.62 (1H, m), 3.40 (3H, s), 3.07-2.94 (2H, m), 2.89-2.81 (1H,m), 2.70-2.50 (1H, m)

MS: 591 (M+H)⁺

Example 2272-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-(2-methoxyethyl)benzamide(compound 227)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, N-methoxyethylamine was used for the similarprocedure as in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ8.74 (1H, t, 5.4 Hz), 7.96 (1H, dd, 8.4, 2.3 Hz), 7.88(1H, d, 2.3 Hz), 7.85 (1H, br), 7.80 (1H, d, 8.4 Hz), 7.28-7.22 (2H, m),6.98 (1H, d, 9.5 Hz), 4.87 (1H, d, 17.5 Hz), 4.54 (1H, d, 17.5 Hz), 3.75(3H, s), 3.71-3.61 (1H, m), 3.50-3.35 (4H, m), 3.28 (3H, s), 3.09-2.94(2H, m), 2.84 (1H, dd, 14.3, 5.4 Hz), 2.60-2.50 (1H, m)

MS: 558 (M+H)³⁰

Example 2282-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-(2-hydroxyethyl)-N-methylbenzamide(compound 228)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, N-methyl-2-hydroxyethylamine was used for thesimilar procedure as in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ7.99-7.90 (2H, m), 7.89-7.80 (2H, m), 7.28-7.20 (2H, m),6.97 (1H, dd, 8.5, 2.2 Hz), 4.93-4.72 (2H, m), 4.54 (0.5H, d, 17.5 Hz),4.52 (0.5H, d, 17.5 Hz), 3.75 (3H, s), 3.74-3.60 (2H, m), 3.59-3.45 (1H,m), 3.43-3.28 (2H, m), 3.15-2.92 (2H, m), 3.04 (1.5H, s), 2.84 (1H, dd,14.3, 4.5 Hz), 2.79 (1.5H, s), 2.61-2.46 (1H, m)

MS: 558 (M+H)⁺

Example 2292-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-cyclopropylbenzamide(compound 229)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, cyclopropylamine was used for the similar procedureas in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ8.69 (1H, d, 4.2 Hz), 7.96 (1H, dd, 8.6, 2.3 Hz), 7.89(1H, d, 2.3 Hz), 7.86 (1H, br), 7.79 (1H, d, 8.6 Hz), 7.29-7.25 (2H, m),6.98 (1H, d, 9.5 Hz), 4.87 (1H, d, 17.6 Hz), 4.55 (1H, d, 17.6 Hz), 3.75(3H, s), 3.72-3.62 (1H, m), 3.09-2.96 (2H, m), 2.90-2.81 (2H, m),2.60-2.50 (1H, m), 0.75-0.70 (1H, m), 0.59-0.54 (1H, m)

MS: 540 (M+H)⁺

Example 2302-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-phenylbenzamide(compound 230)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, aniline was used for the similar procedure as inExample 220 to obtain the title compound.

NMR (DMSO-d₆): δ10.68 (1H, s), 8.10 (1H, d, 2.3 Hz), 8.04 (1H, dd, 8.5,2.3 Hz), 7.91-7.87 (1H, m), 7.88 (1H, d, 8.5 Hz), 7.70 (2H, d, 7.7 Hz),7.37 (2H, t, 7.7 Hz), 7.29-7.21 (2H, m), 7.14 (1H, t, 7.7 Hz), 6.98 (1H,d, 9.5 Hz), 4.88 (1H, d, 17.5 Hz), 4.57 (1H, d, 17.5 Hz), 3.75 (3H, s),3.73-3.62 (1H, m), 3.09-2.95 (2H, m), 2.86 (1H, dd, 14.5, 4.8 Hz),2.60-2.50 (1H, m)

MS: 576 (M+H)⁺

Example 2312-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-cyclohexylbenzamide(compound 231)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, cyclohexylamine was used for the similar procedureas in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ8.53 (1H, d, 7.8 Hz), 7.95 (1H, dd, 8.5, 2.2 Hz),7.89-7.81 (2H, m), 7.79 (1H, d, 8.5 Hz), 7.29-7.22 (2H, m), 6.98 (1H, d,9.5 Hz), 4.88 (1H, d, 17.4 Hz), 4.54 (1H, d, 17.4 Hz), 3.80-3.65 (2H,m), 3.75 (3H, s), 3.08-2.95 (2H, m), 2.84 (1H, dd, 14.3, 4.6 Hz),2.60-2.50 (1H, m), 1.90-1.80 (2H, m), 1.79-1.69 (2H, m), 1.60-1.55 (2H,m), 1.38-1.10 (1H, m)

MS: 582 (M+H)⁺

Example 2322-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-(2-pyridyl)benzamide(compound 232)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, 2-aminopyridine was used for the similar procedureas in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ11.24 (1H, s), 8.40-8.36 (0.6H, m), 8.25-8.15 (0.6H, m),8.10 (1H, s), 7.90-7.84 (3H, m), 7.82-7.70 (0.4H, m), 7.68-7.60 (0.4H,m), 7.29-7.18 (3H, m), 7.00-6.95 (1H, m), 4.87 (0.4H, d, 17.4 Hz), 4.86(0.6H, d, 17.5 Hz), 4.59-4.49 (1H, m), 3.75 (3H, s), 3.72-3.61 (1H, m),3.10-2.95 (2H, m), 2.90-2.80 (1H, m), 2.60-2.50 (1H, m)

MS: 577 (M+H)⁺

Example 2332-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-N-(2-pyridylmethyl)benzamide(compound 233)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, 2-picolylamine was used for the similar procedureas in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ9.28 (1H, t, 5.9 Hz), 8.53 (1H, d, 4.6 Hz), 8.02-7.98(2H, m), 7.89-7.79 (3H, m), 7.44 (1H, d, 7.8 Hz), 7.30 (1H, dd, 7.4, 4.6Hz), 7.28-7.24 (2H, m), 6.98 (1H, d, 9.5 Hz), 4.88 (1H, d, 17.5 Hz),4.59-4.53 (3H, m), 3.75 (3H, s), 3.72-3.64 (1H, m), 3.09-2.94 (2H, m),2.85 (1H, dd, 14.2, 4.6 Hz), 2.59-2.49 (1H, m)

MS: 591 (M+H)⁺

Example 234N-(benzyloxo)-2-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}benzamide(compound 234)

Instead of the starting material of Example 220, that is, the compound119, the compound 197 was used, while instead of the glycine tert-butylester hydrochloride, O-benzylhydroxylamine hydrochloride was used forthe similar procedure as in Example 220 to obtain the title compound.

NMR (DMSO-d₆): δ11.82 (1H, s), 8.00 (1H, d, 8.4, 2.0 Hz), 7.92 (1H, d,2.0 Hz), 7.87 (1H, br), 7.82 (1H, d, 8.4 Hz), 7.47 (2H, d6.9 Hz),7.45-7.38 (3H, m), 7.29-7.24 (2H, m), 6.98 (1H, d, 9.5 Hz), 4.97 (2H,s), 4.86 (1H, d, 17.6 Hz), 4.54 (1H, d, 17.6 Hz), 3.75 (3H, s),3.70-3.64 (1H, m), 3.10-2.95 (2H, m), 2.85 (1H, dd, 14.2, 4.4 Hz),2.60-2.50 (1H, m)

MS: 606 (M+H)⁺

Example 235N-[(1R)-2-anilino-1-methyl-2-oxoethyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 235)

Instead of the starting material of Example 220, that is, the compound119, the compound 100 was used, while instead of the glycine tert-butylester hydrochloride, aniline was used for the similar procedure as inExample 220 to obtain the title compound.

NMR (CDCl₃): δ9.50 (0.5H, d, 6.8 Hz), 9.42 (0.5H, d, 6.9 Hz), 8.32(0.5H, s), 8.23 (0.5H, s), 7.56-7.52 (2H, m), 7.34-7.29 (2H, m),7.24-7.20 (1H, m), 7.15-7.10 (2H, m), 6.81 (0.5H, d, 8.7 Hz), 6.80(0.5H, d, 8.8 Hz), 5.71 (0.5H, br), 5.69 (0.5H, br), 5.40 (0.5H, d, 17.5Hz), 5.36 (0.5H, d, 17.5 Hz), 4.59-4.49 (1H, m), 4.17 (1H, d, 17.5 Hz),3.84 (1.5H, s), 3.83 (1.5H, s), 3.75-3.65 (1H, m), 3.39-3.30 (2H, m),3.25-3.19 (1H, m), 2.67-2.59 (1H, m), 1.537 (1.5H, d, 7.1 Hz), 1.530(1.5H, d, 7.0 Hz)

MS: 473 (M+H)⁺

Example 236N-[(1R)-1-(anilinocarbonyl)propyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 236)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, aniline was used for the similarprocedure as in Example 220 to obtain the title compound.

NMR (CDCl₃): δ9.51 (0.5H, d, 7.3 Hz), 9.43 (0.5H, d, 6.9 Hz), 8.20(0.5H, s), 8.15 (0.5H, s), 7.53 (2H, d, 8.0 Hz), 7.34-7.29 (2H, m), 7.21(1H, dd, 8.7, 2.6 Hz), 7.15-7.00 (2H, m), 6.81 (0.5H, d, 8.7 Hz), 6.80(0.5H, d, 8.7 Hz), 5.85-5.78 (1H, m), 5.36 (0.5H, d, 17.4 Hz), 5.33(0.5H, d, 17.4 Hz), 4.41-4.33 (1H, m), 4.16 (0.5H, d, 17.4 Hz), 4.15(0.5H, d, 17.4 Hz), 3.84 (1.5H, s), 3.83 (1.5H, s), 3.77-3.65 (1H, m),3.37-3.30 (2H, m), 3.25-3.16 (1H, m), 2.65-2.55 (1H, m), 2.10-1.99 (1H,m), 1.91-1.79 (1H, m), 1.10-1.00 (3H, m)

MS: 487 (M+H)⁺

Example 2376-(5-chloro-2-methoxybenzyl)-N-{(1R)-1-[(methylamino)carbonyl]propyl}-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 237)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, a methylamine 30% ethanolsolution was used for the similar procedure as in Example 220 to obtainthe title compound.

NMR (CDCl₃): δ9.40 (0.5H, d, 7.2 Hz), 9.35 (0.5H, d, 7.2 Hz), 7.24-7.20(1H, m), 7.14 (0.5H, d, 2.6 Hz), 7.11 (0.5H, d, 2.5 Hz), 6.81 (1H, d,8.8 Hz), 6.06 (1H, br), 5.77 (1H, br), 5.35 (0.5H, d, 17.7 Hz), 5.32(0.5H, d, 17.7 Hz), 4.28-4.18 (1H, m), 4.14 (1H, d, 17.7 Hz), 3.83 (3H,s), 3.76-3.67 (1H, m), 3.38-3.30 (2H, m), 3.25-3.18 (1H, m), 2.83 (1.5H,s), 2.82 (1.5H, s), 2.66-2.57 (1H, m), 2.00-1.90 (1H, m), 1.83-1.73 (1H,m), 1.03-0.94 (3H, m)

MS: 425 (M+H)⁺

Example 2386-(5-chloro-2-methoxybenzyl)-N-{(1R)-1-[(methylanilino)carbonyl]propyl}-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 238)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, N-methylaniline was used for thesimilar procedure as in Example 220 to obtain the title compound.

NMR (CDCl₃): δ9.54 (0.5H, d, 7.7 Hz), 9.41 (0.5H, d, 7.1 Hz), 7.49-7.11(7H, m), 6.81 (0.5H, d, 8.7 Hz), 6.80 (0.5H, d, 8.7 Hz), 5.72-5.66 (1H,m), 5.36 (0.5H, d, 17.4 Hz), 5.32 (0.5H, d, 17.4 Hz), 4.58-4.49 (0.5H,m), 4.48-4.00 (0.5H, m), 4.10 (1H, d, 17.4 Hz), 3.84 (1.5H, s), 3.82(1.5H, s), 3.74-3.62 (1H, m), 3.42-3.13 (3H, m), 3.30 (1.5H, s), 3.29(1.5H, s), 2.72-2.53 (1H, m), 2.05-1.81 (1H, m), 1.77-1.60 (1H, m),0.85-0.74 (3H, m)

MS: 501 (M+H)⁺

Example 2396-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-{(1R)-1-[(1H-tetrazol-5-ylamino)carbonyl]propyl}-1,4-diazepan-1-carboxamide(compound 239)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, 5-amino-1H-tetrazole was usedfor the similar procedure as in Example 220 to obtain the titlecompound.

NMR (DMSO-d₆): δ15.90 (1H, brs), 12.10 (1H, brs), 9.52-9.47 (1H, m),7.67 (1H, br), 7.31 (1H, s), 7.249 (0.5H, d, 8.8 Hz), 7.243 (0.5H, d,8.8 Hz), 6.98 (1H, d, 8.8 Hz), 4.75 (1H, d, 17.2 Hz), 4.56-4.46 (1H, m),4.52 (1H, d, 17.2 Hz), 3.94-3.84 (1H, m), 3.77 (3H, s), 3.18-2.90 (3H,m), 2.68-2.58 (1H, m), 1.89-1.63 (2H, m), 0.90-0.75 (3H, m)

MS: 479 (M+H)⁺

Melting point: 141-142° C.

Example 2406-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-{(1R)-1-[(2-pyridylamino)carbonyl]propyl}-1,4-diazepan-1-carboxamide(compound 240)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, 2-aminopyridine was used for thesimilar procedure as in Example 220 to obtain the title compound.

NMR (CDCl₃): δ9.59 (0.5H, d, 6.7 Hz), 9.54 (0.5H, d, 6.6 Hz), 8.49 (1H,s), 8.29-8.26 (1H, m), 8.23 (1H, d, 8.6 Hz), 7.71 (0.5H, d, 7.1 Hz),7.69 (0.5H, d, 7.1 Hz), 7.24-7.19 (1H, m), 7.15 (0.5H, d, 2.5 Hz), 7.12(0.5H, d, 2.6 Hz), 7.07-7.03 (1H, m), 6.82 (0.5H, d, 8.7 Hz), 6.81(0.5H, d, 8.7 Hz), 5.84-5.77 (1H, m), 5.40 (0.5H, d, 17.1 Hz), 5.39(0.5H, d, 17.1 Hz), 4.49-4.40 (1H, m), 4.16 (1H, d, 17.1 Hz), 3.85(1.5H, s), 3.84 (1.5H, s), 3.75-3.65 (1H, m), 3.40-3.29 (2H, m),3.28-3.19 (1H, m), 2.70-2.58 (1H, m), 2.11-2.00 (1H, m), 1.97-1.81 (1H,m), 1.10-1.02 (3H, m)

MS: 488 (M+H)⁺

Example 241N-{(1R)-1-[(tert-butoxyamino)carbonyl]propyl}-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 241)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, O-(tert-butyl)hydroxylaminehydrochloride was used for the similar procedure as in Example 220 toobtain the title compound.

NMR (CDCl₃): δ9.34 (0.5H, d, 7.4 Hz), 9.28 (0.5H, d, 7.4 Hz), 8.42 (1H,s), 7.19 (1H, dd, 8.8, 2.5 Hz), 7.12 (0.5H, d, 2.5 Hz), 7.09 (0.5H, d,2.5 Hz), 6.794 (0.5H, d, 8.8 Hz), 6.790 (0.5H, d, 8.8 Hz), 5.69 (1H,br), 5.31 (0.5H, d, 17.6 Hz), 5.28 (0.5H, d, 17.6 Hz), 4.15-4.01 (1H,m), 4.12 (1H, d, 17.6 Hz), 3.82 (1.5H, s), 3.81 (1.5H, s), 3.74-3.62(1H, m), 3.55-3.25 (2H, m), 3.23-3.12 (1H, m), 2.63-2.53 (1H, m),2.02-1.91 (1H, m), 1.83-1.72 (1H, m), 1.25 (9H, s), 1.01-0.95 (3H, m)

MS: 483 (M+H)⁺

Example 2426-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-{(1R)-1-[(3-pyridylamino)carbonyl]propyl}-1,4-diazepan-1-carboxamide(compound 242)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, 3-aminopyridine was used for thesimilar procedure as in Example 220 to obtain the title compound.

NMR (CDCl₃): δ9.51 (0.5H, d, 7.2 Hz), 9.42 (0.5H, d, 6.8 Hz), 8.63-8.58(2H, m), 8.31 (0.5H, s), 8.30 (0.5H, s), 8.15-8.10 (1H, m), 7.24-7.18(2H, m), 7.13 (0.5H, d, 2.6 Hz), 7.10 (0.5H, d, 2.6 Hz), 6.795 (0.5H, d,8.8 Hz), 6.791 (0.5H, d, 8.7 Hz), 5.88 (1H, br), 5.32 (0.5H, d, 17.5Hz), 5.29 (0.5H, d, 17.5 Hz), 4.44-4.32 (1H, m), 4.17 (1H, d, 17.5 Hz),3.82 (1.5H, s), 3.81 (1.5H, s), 3.75-3.65 (1H, m), 3.35-3.26 (2H, m),3.22-3.15 (1H, m), 2.65-2.55 (1H, m), 2.10-1.98 (1H, m), 1.90-1.77 (1H,m), 1.08-0.99 (3H, m)

MS: 488 (M+H)⁺

Example 2436-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-{(1R)-1-[(4-pyridylamino)carbonyl]propyl}-1,4-diazepan-1-carboxamide(compound 243)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, 4-aminopyridine was used for thesimilar procedure as in Example 220 to obtain the title compound.

NMR (CDCl₃): δ9.50 (0.5H, d, 7.1 Hz), 9.41 (0.5H, d 6.8 Hz), 8.79 (0.5H,s), 8.76 (0.5H, s), 8.46 (2H, d, 6.0 Hz), 7.48 (1H, d, 6.0 Hz), 7.47(1H, d, 6.0 Hz), 7.20 (1H, dd, 8.7, 2.5 Hz), 7.13 (0.5H, d, 2.5 Hz),7.11 (0.5H, d, 2.5 Hz), 6.797 (0.5H, d, 8.7 Hz), 6.792 (0.5H, d, 8.7Hz), 5.85 (1H, brd, 8.4 Hz), 5.32 (0.5H, d, 17.4 Hz), 5.29 (0.5H, d,17.4 Hz), 4.39-4.30 (1H, m), 4.17 (1H, d, 17.4 Hz), 3.82 (1.5H, s), 3.81(1.5H, s), 3.80-3.65 (1H, m), 3.35-3.30 (2H, m), 3.22-3.12 (1H, m),2.66-2.56 (1H, m), 2.09-1.98 (1H, m), 1.89-1.79 (1H, m), 1.08-1.00 (3H,m)

MS: 488 (M+H)⁺

Example 244N-((1R)-1-{[3-(aminosulfonyl)anilino]carbonyl}propyl)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 244)

Instead of the starting material compound of Example 220, that is,glycine tert-butyl ester hydrochloride, 3-aminobenzenesulfonamide wasused for the similar procedure as in Example 220 to obtain the titlecompound.

NMR (DMSO-d₆): δ10.47 (0.5H, s), 10.45 (0.5H, s), 9.48 (0.5H, d, 7.2Hz), 9.44 (0.5H, d, 7.3 Hz), 8.18 (0.5H, s), 8.16 (0.5H, s), 7.72-7.66(2H, m), 7.52-7.46 (2H, m), 7.37-7.29 (3H, m), 7.248 (0.5H, d, 8.8 Hz),7.241 (0.5H, d, 8.8 Hz), 6.98 (1H, d, 8.8 Hz), 4.77 (1H, d, 17.1 Hz),4.11 (1H, d, 17.1 Hz) 4.46-4.38 (1H, m), 3.93-3.82 (1H, m), 3.77 (3H,s), 3.18-3.07 (1H, m), 3.05-2.91 (2H, m), 2.69-2.60 (1H, m), 1.89-1.65(2H, m), 0.91-0.80 (3H, m)

MS: 566 (M+H)⁺

Example 245{[2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}aceticacid (compound 245)

A mixed solution of the compound 220 (33 mg) and 1N hydrogenchloride/acetic acid solution (2 ml) was stirred at room temperature for5 hours. The reaction solution was concentrated, then the residue wasdiluted with ethyl acetate. The insoluble compound was filtered out,then the filtrate was concentrated. The residue was recrystallized fromhexane/ethyl acetate to obtain the title compound (18 mg).

NMR (CDCl₃): δ9.42 (0.5H, d, 7.4 Hz), 9.39 (0.5H, d, 6.9 Hz), 7.25-7.05(3.5H, m), 6.80 (1H, d, 8.9 Hz), 6.36 (0.5H, br), 5.28-5.16 (1H, m),4.41-3.90 (5H, m), 3.83 (3H, s), 3.78-3.68 (1H, m), 3.38-3.30 (2H, m),3.22-3.14 (1H, m), 3.67-3.55 (1H, m), 2.00-1.90 (1H, m), 1.85-1.74 (1H,m), 1.05-0.99 (3H, m)

MS: 469 (M+H)⁺

Reference Example 174 3-amino-2-benzylpropanoic acid ethyl hydrochloride(compound S174)

To the (2E)-3-phenyl-2-cyano-2-propenoic acid ethyl (3 g) obtained byusing benzaldehyde instead of the starting material compound ofReference Example 39, that is, the compound S1 for the similar procedureas with Reference Example 39, ethanol (100 ml), platinum oxide (170 mg),and 1N hydrochloric acid/acetic acid solution (20 ml) were added and themixture was stirred under hydrogen atmosphere. The insolubles in thereaction solution were filtered out, the filtrate was concentrated, theresidue was diluted with tetrahydrofuran (100 ml), tert-butyldicarbonate(3.4 g) and triethylamine (4.2 ml) were added, and the mixture wasstirred at room temperature for 30 minutes. A small amount ofN,N-dimethylethylenediamine was added, the mixture was stirred for 5minutes, then the reaction solution was diluted with ethyl acetate andsuccessively washed with 10% citric acid aqueous solution, water,saturated sodium hydrogencarbonate aqueous solution, and saturatedsaline. The organic layer was dried over with anhydrous sodium sulfate,the concentrated. To the ethyl2-benzyl-3-[(tert-butoxycarbonyl)amino]propanoate (2.52 g) obtained byrefining the obtained residue by silica gel column chromatography(hexane/ethyl acetate=7/1 to 5/1), 1M hydrogen chloride/acetic acidsolution (15 ml) was added and the mixture was stirred at roomtemperature for 5 hours. The reaction solution was concentrated toobtain the title compound as a crude product (2.32 g).

Reference Example 1753-[(allyloxycarbonyl)(2-tert-butoxycarbonylmethyl)amino]-2-benzylpropanoicacid (compound S175)

To the compound S174 (2.32 g), methylene chloride (15 ml), saturatedsodium hydrogencarbonate aqueous solution (15 ml), and allylchloroformate (0.92 ml) were added and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was separated, the aqueouslayer was extracted with chloroform. Then, the combined organic layerwas successively washed with a 10% citric acid aqueous solution, water,saturated sodium hydrogencarbonate aqueous solution, and saturatedsaline, then was dried over with anhydrous sodium sulfate andconcentrated. To 1.5 g of the obtained residue, dimethylformamide (15ml), tert-butyl bromoacetate (1.1 ml), and sodium hydride (224 mg) weresuccessively added under ice cooling and the mixture was stirred at roomtemperature for 2 hours. Ammonium chloride aqueous solution was added tothe reaction solution, and the mixture was extracted with hexane-ethylacetate (1:1). The combined extract was successively washed with waterand saturated saline, dried over with anhydrous sodium sulfate, andconcentrated, and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate). To the thus obtained ethyl3-[(allyloxycarbonyl)(2-tert-butoxycarbonylmethyl)amino]-2-benzylpropenoate(968 mg), ethanol (16 ml) and 2N sodium hydroxide aqueous solution (4ml) were added and the mixture was stirred at room temperature for 1.5hours. The reaction solution was diluted with ethyl acetate, acidifiedby 2N hydrochloric acid, then separated. The organic layer was washedwith saturated saline, then dried over with anhydrous sodium sulfate andconcentrated to obtain the title compound (877 mg).

Example 246[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]aceticacid (compound 246)

To thetert-butyl[(2-benzyl-3-{[(4-chlorophenyl)sulfonyl]amino-}-3-oxopropyl)(3-butenoyl)amino]acetate(505 mg), synthesized by using, instead of the starting materialcompound of Reference Example 117, that is, the compound S6, thecompound S175 for the similar procedure as in Reference Example 117, intetrahydrofuran (10 ml) solution, tetrakis(triphenylphosphine)palladium(0) (104 mg) and dimedone (1 g) were added and the mixture was stirredat room temperature for 1 hour. The reaction solution was concentratedand suspended in methanol-diethylether, and the precipitate wascollected by filtration. The collected precipitate was used for thesimilar procedure was followed as in Reference Example 124, Example 1,and Example 251 to obtain the title compound.

NMR (CDCl₃): δ7.94 (2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.25-7.08(5H, m), 4.91 (1H, d, J=17.5 Hz), 4.84 (1H, d, J=17.5 Hz), 4.01 (1H, d,J=17.5 Hz), 3.94 (1H, d, J=17.5 Hz), 3.85-3.70 (1H, m), 3.37-3.26 (2H,m), 3.07 (1H, dd, J=14.2, 5.6 Hz), 2.56 (1H, dd, J=14.2, 7.9 Hz)

MS: 451 (M+H)⁺

Reference Example 1763-[(allyloxycarbonyl)(2-tert-butoxycarbonylethyl)amino]-2-benzylpropanoicacid (compound S176)

To the compound S174 (2.32 g), ethanol (25 ml), triethylamine (1.4 ml),and tert-butyl acrylate (1.3 ml) were added and the mixture refluxed for3 hours. This was cooled, then concentrated, then methylene chloride (15ml), saturated sodium hydrogencarbonate aqueous solution (15 ml), andallyl chloroformate (0.92 ml) were added and the mixture was stirred atroom temperature for 1 hour. The reaction solution was separated, theaqueous layer was extracted with chloroform, then the combined organiclayer was successively washed with a 10% citric acid aqueous solution,water, saturated sodium hydrogencarbonate aqueous solution, andsaturated saline. The organic layer was dried over with anhydrous sodiumsulfate and concentrated, and the obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1). To1.94 g of the thus obtained ethyl3-[(allyloxycarbonyl)(2-tert-butoxycarbonylethyl)amino]-2-benzylpropanoate(2.52 g), ethanol (40 ml) and 2N sodium hydroxide aqueous solution (10ml) were added and the mixture was stirred at room temperature for 1.5hours. The reaction solution was diluted with ethyl acetate, acidifiedby 2N hydrochloric acid, then separated. The organic layer was washedwith saturated saline, then dried over with anhydrous sodium sulfate andconcentrated to obtain the title compound as a crude product (1.82 g).

Example 2473-[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]propanoicacid (compound 247)

Instead of the starting material compound of Reference Example 117, thatis, the compound S6, the compound S176 was used for the similarprocedure as in Reference Example 117 and Example 246 to obtain thetitle compound.

NMR (CDCl₃): δ7.95 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 7.33-7.22(3H, m), 7.13 (2H, d, J=6.8 Hz), 4.89 (1H, d, J=17.5 Hz), 4.48 (1H, d,J=17.5 Hz), 3.57-3.30 (5H, m), 3.19 (1H, dd, J=14.3, 4.2 Hz), 2.60 (1H,dd, J=14.3, 7.8 Hz), 2.50-2.44 (2H, m)

MS: (M+H)⁺

Example 2486-(5-chloro-2-methoxybenzyl)-4-{[4-chloro-3-(1-piperadinylcarbonyl)phenyl]sulfonyl}-1,4-diazepan-2,5-dionehydrochloride (compound 248)

Instead of the starting material of Example 245, that is, the compound220, the compound 223 was used for the similar procedure as in Example245 to obtain the title compound.

NMR (DMSO-d₆): δ9.16 (2H, br), 8.14 (1H, d, 2.2 Hz), 7.99 (1H, d, 8.6Hz), 7.89-7.85 (2H, m), 7.27-7.19 (2H, m), 6.98 (1H, d, 8.8 Hz),4.92-4.81 (1H, m), 4.53 (1H, d, 17.4 Hz), 4.12-3.97 (1H, m), 3.82-3.60(2H, m), 3.75 (3H, s) 3.45-3.10 (4H, m), 3.08-2.91 (4H, m), 2.89-2.76(1H, m), 2.62-2.50 (1H, m)

MS: 569 (M+H)⁺

Example 249[4-chloro-2-({1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-6-yl}methyl)phenoxy]aceticacid (compound 249)

Instead of the starting material compound of Example 29, that is, thecompound 1, the compound 206 was used for the similar procedure as inExample 29 and Example 245 to obtain the title compound.

NMR (DMSO-d₆): δ7.92 (2H, d, J=8.6 Hz), 7.86-7.81 (1H, br), 7.73 (2H, d,J=8.6 Hz), 7.24-7.18 (2H, m), 6.94 (1H, d, J=8.6 Hz), 4.81 (1H, d,J=17.5 Hz), 4.73 (2H, dd, J=22.8, 16.5 Hz), 4.52 (1H, d, J=17.5 Hz),3.98-3.90 (1H, m), 3.10-2.85 (3H, m)

MS: 501 (M+H)⁺

Example 2504-[(3-amino-4-methoxyphenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-1,4-diazepan-2,5-dionehydrochloride (compound 250)

Instead of the starting material of Example 245, that is, the compound220, the compound S1 was used for the similar procedure as in Example245 to obtain the title compound.

NMR (DMSO-d₆): δ7.79 (1H, br), 7.29-7.23 (3H, m), 7.17 (1H, d, 8.6 Hz),7.03-6.96 (2H, m), 4.81 (1H, d, 17.5 Hz), 4.48 (1H, d, 17.5 Hz), 3.87(3H, s), 3.75 (3H, s), 3.69-3.59 (1H, m), 3.01-2.95 (2H, m), 2.84 (1H,dd, 14.2, 4.7 Hz), 2.55-2.50 (1H, m)

MS: 468 (M+H)⁺

Example 2516-(5-chloro-2-methoxybenzyl)-N-{(1R)-1-[(hydroxyamino)carbonyl]propyl}-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 251)

To the compound 241 (30 mg), methylene chloride (1 ml) andtrifluoroacetic acid (0.7 ml) were added and reacted for 6 days. Thereaction solution was concentrated, hexane-ethyl acetate was added, andthe precipitated crystal was collected by filtration to obtain the titlecompound (15 mg).

NMR (DMSO-d₆): δ10.79-10.65 (1H, br), 9.31 (0.5H, d, 7.4 Hz), 9.30(0.5H, d, 7.7 Hz), 8.90 (1H, br), 7.64 (1H, br), 7.30 (0.5H, s), 7.29(0.5H, s), 7.24 (0.5H, d, 8.8 Hz), 7.23 (0.5H, d, 8.8 Hz), 6.97 (1H, d,8.8 Hz), 4.77 (0.5H, d, 17.0 Hz), 4.75 (0.5H, d, 17.0 Hz), 4.49 (1H, d,17.0 Hz), 4.10-4.02 (1H, m), 3.90-3.80 (1H, m), 3.76 (3H, s), 3.15-3.06(1H, m), 3.04-2.88 (2H, m), 2.66-2.57 (1H, m), 1.72-1.52 (2H, m),0.87-0.74 (3H, m)

MS: 427 (M+H)⁺

Example 252(2S)-2-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}propanoicacid (compound 252)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, L-alanine tert-butyl esterhydrochloride was used for the similar procedure as in Example 220 andExample 245 to obtain the title compound.

NMR (DMSO-d₆): δ12.79-12.19 (1H, br), 9.40 (0.5H, d, 7.5 Hz), 9.35(0.5H, d, 7.7 Hz), 8.45 (0.5H, d, 8.0 Hz), 8.43 (0.5H, d, 8.0 Hz), 7.64(1H, br), 7.307 (0.5H, s), 7.301 (0.5H, s), 7.24 (0.5H, d, 8.8 Hz), 7.23(0.5H, d, 8.8 Hz), 6.97 (1H, d, 8.8 Hz), 4.78 (0.5H, d, 17.0 Hz), 4.76(0.5H, d, 17.0 Hz), 4.48 (1H, d, 17.0 Hz), 4.35-4.28 (1H, m), 4.25-4.15(1H, m), 3.89-3.80 (1H, m), 3.76 (3H, s), 3.15-3.08 (1H, m), 3.03-2.91(2H, m), 2.65-2.58 (1H, m), 1.72-1.57 (2H, m), 1.23 (3H, d, 7.3 Hz),0.82-0.75 (3H, m)

MS: 483 (M+H)⁺

Example 253(2R)-2-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}propanoicacid (compound 253)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, D-alanine tert-butyl esterhydrochloride was used for the similar procedure as in Example 220 andExample 245 to obtain the title compound.

NMR (DMSO-d₆): δ12.75-12.21 (1H, br), 9.37 (0.5H, d, 7.4 Hz), 9.33(0.5H, d, 7.7 Hz), 8.41 (0.5H, d, 7.6 Hz), 8.39 (0.5H, d, 8.0 Hz), 7.64(1H, br), 7.30 (0.5H, s), 7.29 (0.5H, s), 7.24 (0.5H, d, 8.8 Hz), 7.23(0.5H, d, 8.8 Hz), 6.97 (1H, d, 8.8 Hz), 4.77 (0.5H, d, 17.1 Hz), 4.76(0.5H, d, 17.1 Hz), 4.48 (1H, d, 17.1 Hz), 4.35-4.26 (1H, m), 4.23-4.13(1H, m), 3.89-3.80 (1H, m), 3.76 (3H, s), 3.16-3.05 (1H, m), 3.04-2.91(2H, m), 2.67-2.57 (1H, m), 1.75-1.55 (2H, m), 1.25 (1.5H, d, 7.4 Hz),1.24 (1.5H, d, 7.3 Hz), 0.88-0.81 (3H, m)

MS: 483 (M+H)⁺

Example 254N-{(1R)-1-[(3-aminoanilino)carbonyl]propyl}-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 254)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride,1-(tert-butoxycarbonyl)-1,3-phenylenediamine was used for the similarprocedure as in Example 220 and Example 245 to obtain the titlecompound.

NMR (DMSO-d₆): δ9.83 (0.5H, s), 9.81 (0.5H, s), 9.45 (0.5H, d, 7.4 Hz),9.41 (0.5H, d, 7.4 Hz), 7.65 (1H, d, 2.9 Hz), 7.316 (0.5H, s), 7.311(0.5H, s), 7.24 (0.5H, d, 8.8 Hz), 7.23 (0.5H, d, 8.8 Hz), 6.98 (1H, d,8.8 Hz), 6.91-6.87 (2H, m), 6.64 (1H, d, 7.8 Hz), 6.23 (1H, d, 7.8 Hz),5.02 (2H, s), 4.78 (0.5H, d, 17.1 Hz), 4.77 (0.5H, d, 17.1 Hz), 4.50(1H, d, 17.1 Hz), 4.45-4.37 (1H, m), 3.92-3.81 (1H, m), 3.77 (3H, s),3.19-3.08 (1H, m), 3.07-2.91 (2H, m), 2.68-2.60 (1H, m), 1.82-1.65 (2H,m), 0.89-0.82 (3H, m)

MS: 502 (M+H)⁺

Example 2553-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}benzoicacid (compound 255)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, tert-butyl 3-aminobenzoate wasused for the similar procedure as in Example 220 and Example 245 toobtain the title compound.

NMR (DMSO-d₆): δ13.10-12.47 (1H, br), 10.35 (0.5H, s), 10.33 (0.5H, s),9.48 (0.5H, d, 7.2 Hz), 9.43 (0.5H, d, 7.3 Hz), 8.22-8.20 (1H, br), 7.78(1H, d, 7.9), 7.65 (1H, s), 7.61 (1H, d, 7.9 Hz), 7.41 (1H, t, 7.9 Hz),7.31 (1H, s), 7.24 (0.5H, d, 8.8 Hz), 7.23 (0.5H, d, 8.8 Hz), 6.98 (1H,d, 8.8 Hz), 4.78 (0.5H, d, 17.2 Hz), 4.77 (0.5H, d, 17.2 Hz), 4.51 (1H,d, 17.2 Hz), 4.49-4.39 (1H, m), 3.90-3.81 (1H, m), 3.77 (3H, s),3.18-3.07 (1H, m), 3.05-2.91 (2H, m), 2.69-2.60 (1H, m), 1.89-1.67 (2H,m), 0.92-0.80 (3H, m)

MS: 531 (M+H)⁺

Example 256(2S)-2-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}-4-methylpentanoicacid (compound 256)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, L-leucine tert-butyl ester wasused for the similar procedure as in Example 220 and Example 245 toobtain the title compound.

NMR (DMSO-d₆): δ12.81-12.25 (1H, br), 9.40 (0.5H, d, 7.5 Hz), 9.37(0.5H, d, 7.6 Hz), 8.44-8.40 (1H, m), 7.64 (1H, d, 3.6 Hz), 7.309 (0.5H,s), 7.303 (0.5H, s), 7.24 (0.5H, d, 8.8 Hz), 7.23 (0.5H, d, 8.8 Hz),6.97 (1H, d, 8.8 Hz), 4.78 (0.5H, d, 17.0 Hz), 4.75 (0.5H, d, 17.0 Hz),4.48 (1H, d, 17.0 Hz), 4.38-4.30 (1H, m), 4.23-4.17 (1H, m), 3.89-3.80(1H, m), 3.76 (3H, s), 3.14-3.08 (1H, m), 3.00-2.90 (2H, m), 2.68-2.58(1H, m), 1.72-1.42 (5H, m), 0.90-0.85 (3H, m), 0.84-0.75 (6H, m)

MS: 525 (M+H)⁺

Example 2572-amino-5-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}benzoicacid hydrochloride (compound 257)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, tert-butyl 2,5-diaminobenzoatewas used for the similar procedure as in Example 220 and Example 245 toobtain the title compound.

NMR (DMSO-d₆): δ9.92 (0.5H, s), 9.89 (0.5H, s), 9.45 (0.5H, d, 7.4 Hz),9.40 (0.5H, d, 7.4 Hz), 7.95-7.92 (1H, m), 7.66 (0.5H, s), 7.61 (0.5H,s), 7.427 (0.5H, d, 8.7 Hz), 7.421 (0.5H, d, 8.7 Hz), 7.31 (1H, s), 7.24(0.5H, d, 8.8 Hz), 7.23 (0.5H, d, 8.8 Hz), 6.98 (1H, d, 8.8 Hz), 6.71(1H, d, 8.7 Hz), 4.78 (0.5H, d, 17.1 Hz), 4.77 (0.5H, d, 17.1 Hz), 4.50(1H, d, 17.1 Hz), 4.39-4.32 (1H, m), 3.91-3.79 (1H, m), 3.77 (3H, s),3.17-3.07 (1H, m), 3.03-2.92 (2H, m), 2.68-2.60 (1H, m), 1.83-1.65 (2H,m), 0.89-0.81 (3H, m)

MS: 546 (M+H)⁺

Example 258N-{(1R)-1-[(4-aminoanilino)carbonyl]propyl}-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 258)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride,1-(tert-butoxycarbonyl)-1,4-phenylenediamine was used for the similarprocedure as in Example 220 and Example 245 to obtain the titlecompound.

NMR (DMSO-d₆): δ9.72 (0.5H, s), 9.70 (0.5H, s), 9.43 (0.5H, d, 7.4 Hz),9.39 (0.5H, d, 7.5 Hz), 7.65 (1H, d, 3.2 Hz), 7.31 (0.5H, s), 7.30(0.5H, s), 7.24 (0.5H, d, 8.9 Hz), 7.23 (0.5H, d, 8.9 Hz), 7.17 (2H, d,8.6 Hz), 6.98 (1H, d, 8.9 Hz), 6.48 (1H, d, 8.6 Hz), 6.46 (1H, d, 8.6Hz), 4.847 (1H, s), 4.842 (1H, s), 4.79 (0.5H, d, 17.1 Hz), 4.77 (0.5H,d, 17.1 Hz), 4.50 (1H, d, 17.1 Hz), 4.39-4.32 (1H, m), 3.91-3.81 (1H,m), 3.77 (3H, s), 3.18-3.07 (1H, m), 3.03-2.92 (2H, m), 2.68-2.60 (1H,m), 1.80-1.62 (2H, m), 0.89-0.81 (3H, m)

MS: 502 (M+H)⁺

Example 2595-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}-2-hydroxybenzoicacid (compound 259)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, tert-butyl4-amino-2-hydroxybenzoate was used for the similar procedure as inExample 220 and Example 245 to obtain the title compound.

NMR (DMSO-d₆): δ13.78-13.22 (1H, br), 11.43 (0.5H, s), 11.37 (0.5H, s),9.53 (0.5H, d, 6.5 Hz), 9.46 (0.5H, d, 6.6 Hz), 8.46-8.40 (1H, m), 7.95(1H, d, 7.5 Hz), 7.70-7.60 (1H, m), 7.57 (1H, t, 7.5 Hz), 7.35-7.31 (1H,m), 7.28-7.22 (1H, m), 7.15 (1H, t, 7.5 Hz), 6.99 (1H, d, 8.8 Hz), 4.77(0.5H, d, 17.3 Hz), 4.73 (0.5H, d, 17.3 Hz), 4.53 (1H, d, 17.3 Hz),4.31-4.25 (1H, m), 3.95-3.84 (1H, m), 3.77 (3H, s), 3.15-3.06 (1H, m),3.05-2.91 (2H, m), 2.69-2.61 (1H, m), 1.94-1.72 (2H, m), 0.95-0.89 (3H,m)

MS: 547 (M+H)⁺

Example 2602-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}benzoicacid (compound 260)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, tert-butyl anthranilate was usedfor the similar procedure as in Example 220 and Example 245 to obtainthe title compound.

NMR (DMSO-d₆): δ13.78-13.22 (1H, br), 11.43 (0.5H, s), 11.37 (0.5H, s),9.53 (0.5H, d, 6.5 Hz), 9.46 (0.5H, d, 6.6 Hz), 8.46-8.40 (1H, m), 7.95(1H, d, 7.5 Hz), 7.70-7.60 (1H, m), 7.57 (1H, t, 7.5 Hz), 7.35-7.31 (1H,m), 7.28-7.22 (1H, m), 7.15 (1H, t, 7.5 Hz), 6.99 (1H, d, 8.8 Hz), 4.77(0.5H, d, 17.3 Hz), 4.73 (0.5H, d, 17.3 Hz), 4.53 (1H, d, 17.3 Hz),4.31-4.25 (1H, m), 3.95-3.84 (1H, m), 3.77 (3H, s), 3.15-3.06 (1H, m),3.05-2.91 (2H, m), 2.69-2.61 (1H, m), 1.94-1.72 (2H, m), 0.95-0.89 (3H,m)

MS: 531 (M+H)⁺

Example 2614-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}benzoicacid (compound 261)

Instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, tert-butyl 4-aminobenzoate wasused for the similar procedure as in Example 220 and Example 245 toobtain the title compound.

NMR (DMSO-d₆): δ12.88-12.35 (1H, br), 10.47 (0.5H, s), 10.45 (0.5H, s),9.47 (0.5H, d, 7.2 Hz), 9.43 (0.5H, d, 7.3 Hz), 7.87 (2H, d, 8.6 Hz),7.68 (2H, d, 8.6 Hz), 7.67 (1H, br), 7.31 (1H, s), 7.248 (0.5H, d, 8.8Hz), 7.242 (0.5H, d, 8.8 Hz), 6.98 (1H, d, 8.8 Hz), 4.77 (1H, d, 17.1Hz), 4.51 (1H, d, 17.1 Hz), 4.48-4.40 (1H, m), 3.92-3.81 (1H, m), 3.77(3H, s), 3.18-3.08 (1H, m), 3.05-2.92 (2H, m), 2.65-2.59 (1H, m),1.85-1.65 (2H, m), 0.90-0.85 (3H, m)

MS: 531 (M+H)⁺

Example 2624-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}-1H-pyrrole-2-carboxylicacid (compound 262)

To 4-nitropyrrol-2-carboxylic acid (2.0 g), methylene chloride (15 ml),tert-butanol (15 ml), and O-tert-butyl-N,N′-diisopropylisourea (7 ml)were added and the mixture refluxed for 7 hours. The reaction solutionwas concentrated, and the obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=7/3). To the obtained4-nitropyrrole-2-carboxylic acid tert-butyl ester (1.7 g), ethyl acetate(30 ml) and 10% palladium carbon (0.25 g) were added and the mixture wasstirred under hydrogen atmosphere at room temperature for 8 hours. Thereaction solution was filtered, the filtrate was concentrated, and theobtained residue was purified by silica gel column chromatography. Theobtained 4-aminopyrrole-2-carboxylic acid tert-butyl ester was used,instead of the starting material compound of Example 220, that is, theglycine tert-butyl ester hydrochloride, for the similar procedure was inExample 220 and Example 245 to obtain the title compound.

NMR (DMSO-d₆): δ12.30-12.10 (1H, br), 11.46 (1H, s), 10.10 (0.5H, s),10.07 (0.5H, s), 9.44 (0.5H, d, 7.4 Hz), 9.39 (0.5H, d, 7.4 Hz), 7.659(0.5H, s), 7.651 (0.5H, s), 7.315 (0.5H, s), 7.310 (0.5H, s), 7.24(0.5H, d, 8.9 Hz), 7.23 (0.5H, d, 8.9 Hz), 7.15 (1H, s), 6.98 (1H, d,8.9 Hz), 6.61 (1H, s), 4.78 (0.5H, d, 17.1 Hz), 4.76 (0.5H, d, 17.1 Hz),4.50 (1H, d, 17.1 Hz) 4.37-4.29 (1H, m), 3.91-3.80 (1H, m), 3.77 (3H,s), 3.12 (0.5H, t, 13.2 Hz), 3.11 (0.5H, t, 12.8 Hz), 3.03-2.92 (2H, m),2.66-2.51 (1H, m), 1.80-1.62 (2H, m), 0.86-0.80 (3H, m)

MS: 520 (M+H)⁺

Example 2635-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino-}-2-methylbenzoicacid (compound 263)

Instead of the starting material compound of Example 262, that is, the4-nitropyrrole-2-carboxylic acid, 2-methyl-5-nitrobenzoic acid was usedfor the similar procedure as in Example 262 to obtain the titlecompound.

NMR (DMSO-d₆): δ12.91-12.49 (1H, br), 10.24 (0.5H, s), 10.21 (0.5H, s),9.47 (0.5H, d, 7.3 Hz), 9.42 (0.5H, d, 7.4 Hz), 8.07 (0.5H, d, 3.7 Hz),8.06 (0.5H, d, 2.5 Hz), 7.65-7.62 (2H, m), 7.31 (1H, s), 7.26-7.19 (2H,m), 6.98 (1H, d, 8.8 Hz), 4.78 (0.5H, d, 17.2 Hz), 4.77 (0.5H, d, 17.2Hz), 4.50 (1H, d, 17.2 Hz) 4.44-4.36 (1H, m), 3.92-3.81 (1H, m), 3.77(3H, s), 3.18-3.07 (1H, m), 3.05-2.94 (2H, m), 2.66-2.60 (1H, m), 2.29(3H, s), 1.83-1.66 (2H, m), 0.90-0.83 (3H, m)

MS: 545 (M+H)⁺

Melting point: 132-134° C.

Example 2643-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino-}-2-methoxybenzoicacid (compound 264)

To 2-hydroxy-3-nitrobenzoic acid (5.2 g), methylene chloride (30 ml),tert-butanol (30 ml), and O-tert-butyl-N,N′-diisopropylisourea (15 ml)were added and the mixture refluxed for 3 hours. The reaction solutionwas concentrated, and the obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate-20/1 to 6/1). To 430 g ofthe obtained tert-butyl 2-hydroxy-3-nitrobenzoate (1.5 g),N,N′-dimethylformamide (10 ml), methyl iodide (0.13 ml), and potassiumcarbonate (0.29 g) were added and the mixture was stirred at roomtemperature for 5 hours. Water was added to the reaction solution, thenthe mixture was extracted with hexane/ethyl acetate-1/1 solution. Theextract was dried over with anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate-10/1). To the obtained tert-butyl2-methoxy-3-nitrobenzoate (340 mg), ethanol (10 ml) and 10% palladiumcarbon (50 mg) were added and the mixture was stirred under hydrogenatmosphere at room temperature for 18 hours. The reaction solution wasfiltered, the filtrate was concentrated, and the obtained residue waspurified by silica gel column chromatography. The obtained tert-butyl3-amino-2-methoxybenzoate was used instead of the starting materialcompound of Example 220, that is, the glycine tert-butyl esterhydrochloride, for the similar procedure as with Example 220 and Example245 to obtain the title compound.

NMR (DMSO-d₆): δ13.27-12.37 (1H, br), 9.66 (1H, s), 9.45 (0.5H, d, 7.3Hz), 9.42 (0.5H, d, 7.3 Hz), 8.04 (0.5H, t, 8.4 Hz), 8.04 (0.5H, t, 7.0Hz), 7.67 (1H, s), 7.43 (0.5H, d, 7.8 Hz), 7.42 (0.5H, d, 8.1 Hz), 7.319(0.5H, s), 7.312 (0.5H, s), 7.24 (0.5H, d, 8.7 Hz), 7.23 (0.5H, d, 8.7Hz), 7.15-7.10 (1H, m), 6.98 (1H, d, 8.7 Hz), 4.79 (0.5H, d, 17.1 Hz),4.78 (0.5H, d, 17.1 Hz), 4.68-4.62 (1H, m), 4.21 (1H, d, 17.1 Hz),3.91-3.83 (1H, m), 3.77 (3H, s), 3.70 (1.5H, s), 3.69 (1.5H, s),3.17-3.07 (1H, m), 3.03-2.91 (2H, m), 2.68-2.59 (1H, m), 1.88-1.69 (2H,m), 0.94-0.88 (3H, m)

MS: 561 (M+H)⁺

Example 2653-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}-4-methoxybenzoicacid (compound 265)

Instead of the starting material compound of Example 264, that is,2-hydroxy-3-nitrobenzoic acid, 4-hydroxy-3-nitrobenzoic acid was usedfor the similar procedure as in Example 264 to obtain the titlecompound.

NMR (DMSO-d₆): δ12.80-12.40 (1H, br), 9.55 (1H, s), 9.44 (0.5H, d, 7.3Hz), 9.40 (0.5H, d, 7.4 Hz), 8.467 (0.5H, d, 2.2 Hz), 8.460 (0.5H, d,3.2 Hz), 7.72-7.65 (2H, m), 7.318 (0.5H, s), 7.312 (0.5H, s), 7.24 (1H,d, 8.8 Hz), 7.11 (1H, d, 8.6 Hz), 6.98 (1H, d, 8.8 Hz), 4.78 (1H, d,17.4 Hz), 4.65-4.52 (1H, m), 4.51 (1H, d, 17.4 Hz), 3.95-3.82 (1H, m),3.87 (3H, s), 3.77 (3H, s), 3.13 (0.5H, t, 12.9 Hz), 3.11 (0.5H, t, 13.0Hz), 3.03-2.93 (2H, m), 2.67-2.62 (1H, m), 1.84-1.65 (2H, m), 0.93-0.85(3H, m)

MS: 561 (M+H)⁺

Example 2663-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}-4-fluorobenzoicacid (compound 266)

Instead of the starting material compound of Example 262, that is,4-nitropyrrole-2-carboxylic acid, 4-fluoro-3-nitrobenzoic acid was usedfor the similar procedure as in Example 262 to obtain the titlecompound.

NMR (DMSO-d₆): δ12.90-12.20 (1H, br), 10.15 (0.5H, s), 10.14 (0.5H, s),9.47 (0.5H, d, 7.3 Hz), 9.43 (0.5H, d, 7.2 Hz), 8.43 (1H, t, 5.6 Hz),7.75-7.70 (1H, m), 7.65 (1H, s), 7.39-7.31 (2H, m), 7.24 (1H, d, 8.8Hz), 6.98 (1H, d, 8.8 Hz), 4.78 (1H, d, 17.1 Hz), 4.65-4.56 (1H, m),4.51 (1H, d, 17.1 Hz), 3.90-3.82 (1H, m), 3.77 (3H, s), 3.15-3.06 (1H,m), 3.05-2.93 (2H, m), 2.66-2.59 (1H, m), 1.88-1.69 (2H, m), 0.93-0.85(3H, m)

MS: 549 (M+H)⁺

Example 2673-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino-}-4-hydroxybenzoicacid (compound 267)

To the synthesis intermediate of Example 265, that is, tert-butyl4-hydroxy-3-nitrobenzoate (0.42 g), methylene chloride (10 ml),chloromethylmethylether (0.16 ml), and N,N-diisopropylethylamine (0.37ml) were added under ice cooling and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was diluted with ethylacetate and successively washed with water, a potassium hydrogensulfateaqueous solution, and saturated saline. The mixture was dried over withanhydrous magnesium sulfate, then concentrated. The obtained residue waspurified by silica gel column chromatography (hexane/ethylacetate=10/1). To the obtained tert-butyl4-methoxymethyloxy-3-nitrobenzoate (0.26 g), ethanol (10 ml) and 10%palladium carbon (40 mg) were added and the mixture was stirred underhydrogen atmosphere at room temperature for 7 hours. The reactionsolution was filtered, the filtrate was concentrated, and the obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate=6/1 to 1/1). The obtained tert-butyl3-amino-2-methoxymethyloxybenzoate was used, instead of the startingmaterial compound of Example 220, that is, the glycine tert-butyl esterhydrochloride, for the similar procedure as in Example 220 and Example245 to obtain the title compound.

NMR (DMSO-d₆): δ12.58-12.12 (1H, br), 10.6 (1H, s), 9.51 (0.5H, s), 9.50(0.5H, s), 9.45 (0.5H, d, 7.3 Hz), 9.41 (0.5H, d, 7.3 Hz), 8.38 (1H, s),7.65 (1H, s), 7.55 (1H, d, 8.3 Hz), 7.31 (1H, s), 7.24 (1H, d, 8.9 Hz),6.98 (1H, d, 8.8 Hz), 6.90 (1H, d, 8.5 Hz), 4.78 (1H, d, 16.6 Hz),4.65-4.61 (1H, m), 4.50 (1H, d, 17.1 Hz), 3.90-3.83 (1H, m), 3.77 (3H,s), 3.13 (0.5H, t, 12.6 Hz), 3.11 (0.5H, t, 12.4 Hz), 3.02-2.91 (2H, m),2.68-2.60 (1H, m), 1.85-1.66 (2H, m), 0.91-0.85 (3H, m)

MS: 547 (M+H)⁺

Example 2683-amino-5-{[(2R)-2-({[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)butanoyl]amino}benzoicacid (compound 268)

To 3-amino-5-nitrobenzoic acid (2.1 g), 1,4-dioxane (30 ml) anddi-tert-butyldicarbonate (3.74 g) were added and the mixture refluxedfor 3 days. The reaction solution was concentrated and diluted withethyl acetate. The solution was washed with a potassium hydrogensulfateaqueous solution and saturated saline, dried over with anhydrous sodiumsulfate, and concentrated. The thus obtained3-(tert-butoxycarbonylamino)-5-nitrobenzoic acid was used instead of thestarting material compound of Example 262, that is, the4-nitropyrrole-2-carboxylic acid, for the similar procedure as inExample 262 to obtain the title compound.

NMR (DMSO-d₆): δ12.73-11.90 (1H, br), 10.1 (0.5H, s), 10.0 (0.5H, s),9.46 (0.5H, d, 7.3 Hz), 9.42 (0.5H, d, 7.4 Hz), 7.65 (1H, d, 3.2 Hz),7.32-7.22 (3H, m), 7.10 (0.5H, s), 7.09 (0.5H, s), 6.99 (0.5H, s), 6.97(0.5H, s), 6.87 (0.5H, s), 6.86 (0.5H, s), 5.32 (2H, brs), 4.78 (1H, d,17.3 Hz), 4.50 (1H, d, 17.1 Hz), 4.42-4.38 (1H, m), 3.90-3.82 (1H, m),3.77 (3H, s), 3.17-3.07 (1H, m), 3.04-2.93 (2H, m), 2.67-2.62 (1H, m),1.85-1.60 (2H, m), 0.88-0.81 (3H, m)

MS: 546 (M+H)⁺

Example 269methyl[4-chloro-2-({1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-6-yl}methyl)phenoxy]acetate(compound 269)

Instead of the starting material of Example 208, that is, the compound196, the compound 249 was used for the similar procedure as in Example208 to obtain the title compound.

NMR (CDCl₃): δ7.95 (2H, d, J=8.7 Hz), 7.50 (2H, d, J=8.7 Hz), 7.16 (1H,dd, J=8.7, 2.6 Hz), 7.08 (1H, d, J=2.6 Hz), 6.64 (1H, d, J=8.7 Hz),5.81-5.76 (1H, br), 4.98 (1H, d, J=17.5 Hz), 4.66 (2H, s), 4.60 (1H, d,J=17.5 Hz), 3.99-3.87 (1H, m), 3.79 (3H, s), 3.36-3.27 (1H, m),3.20-3.10 (2H, m), 2.56 (1H, dd, J=14.0, 8.4 Hz)

MS: 515 (M+H)⁺

Melting point: 138-140° C.

Example 2702-{6-benzyl-4-[(4-chlorophenyl)sulfonyl]-2,5-dioxo-1,4-diazepan-1-yl}-N-phenylacetoamide(compound 270)

To the compound 246 (14 mg) in N,N-dimethylformamide (0.3 ml) solution,aniline (5 μM), triethylamine (0.03 ml), and n-propylphosphonic acidanhydride (25% ethyl acetate solution) (0.03 ml) were added and themixture was stirred at room temperature for 5 hours. The reactionsolution was diluted with ethyl acetate, successively washed with 1Nhydrochloric acid, saturated saline, saturated sodium hydrogencarbonateaqueous solution, and saturated saline, dried over with anhydrous sodiumsulfate, then concentrated. The residue was recrystallized frommethanol/diethylether to obtain the title compound (8.7 mg).

NMR (DMSO-d₆): δ10.00 (1H, s), 7.94 (2H, d, J=8.6 Hz), 7.70 (2H, d,J=8.6 Hz), 7.50 (2H, d, J=7.9 Hz), 7.34-7.15 (7H, m), 7.05 (1H, t, J=7.3Hz), 5.11 (1H, d, J=17.4 Hz), 7.71 (1H, d, J=17.4 Hz), 4.08 (1H, d,J=16.4 Hz), 4.01-3.90 (1H, m), 3.96 (1H, d, J=16.4 Hz), 3.49-3.25 (2H,m), 2.96 (1H, dd, J=14.3, 5.5 Hz), 2.66-2.47 (1H, m)

MS: 548 (M+Na)⁺

Example 2712-[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]-N-methyl-N-phenylacetoamide(compound 271)

Instead of the starting material compound of Example 270, that is,aniline, N-methylaniline was used for the similar procedure as inExample 270 to obtain the title compound.

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.50-7.35 (5H, m), 7.31-7.20 (5H,m), 7.12 (2H, d, J=6.8 Hz), 4.94 (1H, d, J=17.5 Hz), 4.54 (1H, d, J=17.5Hz), 3.64 (2H, s), 3.53-3.45 (1H, m), 3.32-3.29 (2H, m), 3.23 (3H, s),3.16 (1H, dd, J=14.3, 5.6 Hz), 2.56 (1H, dd, J=14.3, 7.7 Hz)

MS: 540 (M+H)⁺

Example 272N-benzyl-2-[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]acetoamide(compound 272)

Instead of the starting material compound of Example 270, that is,aniline, benzylamine was used for the similar procedure as in Example270 to obtain the title compound.

NMR (CDCl₃): δ7.92 (2H, d, J=8.6 Hz), 7.47 (2H, d, J=8.6 Hz), 7.37-7.19(8H, m), 7.11 (2H, d, J=6.9 Hz), 6.20 (1H, m), 4.95 (1H, d, J=17.6 Hz),4.51 (1H, d, J=17.6 Hz), 4.39 (1H, dd, J=14.8, 5.8 Hz), 4.34 (1H, dd,J=14.8, 5.8 Hz), 3.88 (1H, d, J=15.3 Hz), 3.81 (1H, d, J=15.3 Hz),3.50-3.35 (3H, m), 3.17 (1H, dd, J=14.0, 3.9 Hz), 2.58 (1H, dd, J=14.0,6.3 Hz)

MS: 540 (M+H)⁺

Melting point: 187-190° C.

Example 2733-[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]-N-phenylpropanamide(compound 273)

Instead of the starting material compound of Example 270, that is, thecompound 246, the compound 247 was used for the similar procedure as inExample 270 to obtain the title compound.

NMR (CDCl₃): δ7.89 (2H, d, J=8.7 Hz), 7.84 (1H, brs), 7.49 (2H, d, J=7.9Hz), 7.43 (2H, d, J=8.7 Hz), 7.33 (2H, t, J=7.9 Hz), 7.30-7.19 (3H, m),7.15-7.05 (3H, m), 4.85 (1H, d, J=17.5 Hz), 4.48 (1H, d, J=17.5 Hz),3.69-3.53 (2H, m), 3.48-3.42 (2H, m), 3.38-3.28 (1H, m), 3.15 (1H, dd,J=14.3, 4.9 Hz), 2.61 (1H, dd, J=14.3, 8.1 Hz), 2.53 (2H, t, J=6.3 Hz)

MS: 540 (M+H)⁺

Example 274N-benzyl-3-[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]propanamide(compound 274)

Instead of the starting material compound of Example 273, that is,aniline, benzylamine was used for the similar procedure as in Example273 to obtain the title compound.

NMR (CDCl₃): δ7.94 (2H, d, J=8.7 Hz), 7.46 (2H, d, J=8.7 Hz), 7.38-7.22(8H, m), 7.11 (2H, d, J=8.2 Hz), 5.87 (1H, br), 4.74 (1H, d, J=17.3 Hz),4.45-4.30 (3H, m), 3.64-3.57 (1H, m), 3.52-3.25 (4H, m), 3.13 (1H, dd,J=14.3, 4.9 Hz), 2.63 (1H, dd, J=14.3, 8.0 Hz), 2.31 (2H, t, J=6.5 Hz)

MS: (M+H)⁺

Example 2753-[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]propanamide(compound 275)

Instead of the starting material compound of Example 273, that is,aniline, 1,1,1,3,3,3-hexamethyldisilazane was used for the similarprocedure as in Example 273 to obtain the title compound.

NMR (CDCl₃): δ7.95 (2H, d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz), 7.23-7.21(3H, m), 7.11 (2H, d, J=7.0 Hz), 5.79 (1H, br), 5.34 (1H, br), 4.80 (1H,d, J=17.4 Hz), 4.47 (1H, d, J=17.4 Hz), 3.64-3.55 (1H, m), 3.49-3.40(2H, m), 3.39-3.28 (2H, m), 3.15 (1H, dd, J=14.4, 4.6 Hz), 2.61 (1H, dd,J=14.4, 8.3 Hz), 2.46-2.29 (2H, m)

MS: 464 (M+H)⁺

Example 2763-[6-benzyl-4-(4-chlorobenzenesulfonyl)-2,5-dioxo-1,4-diazepan-1-yl]-N-(3-pyridyl)propanamide(compound 276)

Instead of the starting material compound of Example 273, that is,aniline, 3-aminopyridine was used for the similar procedure as inExample 273 to obtain the title compound.

NMR (DMSO-d₆): δ10.16 (1H, s), 8.66 (1H, d, J=2.1 Hz), 8.25 (1H, d,J=4.7 Hz), 7.97-7.93 (1H, m), 7.88 (2H, d, J=8.6 Hz), 7.70 (2H, d, J=8.6Hz), 7.33 (1H, dd, J=8.2, 4.7 Hz), 7.25-7.12 (5H, m), 4.99 (1H, d,J=17.4 Hz), 4.65 (1H, d, J=17.4 Hz), 3.89-3.78 (1H, m), 3.59-3.49 (1H,m), 3.43-3.30 (4H, m), 2.95 (1H, dd, J=14.2, 5.6 Hz), 2.58-2.43 (2H, m)

MS: 541 (M+H)⁺

Example 2772-[4-chloro-2-({1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-6-yl}methyl)phenoxy]-N-methylacetoamide(compound 277)

Instead of the starting material of Example 270, that is, the compound246, the compound 249 was used, while instead of aniline, methylaminehydrochloride was used for the similar procedure as in Example 270 toobtain the title compound.

NMR (CDCl₃): δ7.94 (2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 7.21 (1H,dd, J=8.7, 2.5 Hz), 7.07 (1H, d, J=2.5 Hz), 6.80-6.75 (1H, br), 6.73(1H, d, J=8.7 Hz), 5.90-5.86 (1H, br), 4.91 (1H, d, J=17 Hz), 4.65 (1H,d, J=17 Hz), 4.48 (2H, s), 33.40-3.22 (3H, m), 2.88 (4H, d, J=4.8 Hz),2.54 (1H, dd, J=13.8, 8.3 Hz)

MS: 514 (M+H)⁺

Example 278 ethyl4-chloro-2-((E)-{1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-6-ylidene}methyl)phenylcarbamate(compound 278)

To the compound 204 (94 mg) in methylene chloride (1.9 ml) solution,pyridine (21 μM) and ethyl chlorocarbonate (25 μM) was added and themixture was stirred at room temperature for 30 minutes. To the reactionsolution, saturated ammonium chloride aqueous solution was added and themixture was extracted with chloroform. The organic layer wassuccessively washed with saturated saline, dried over with anhydroussodium sulfate, then concentrated. The residue was recrystallized fromhexane/ethyl acetate to obtain the title compound (74 mg).

NMR (CDCl₃): δ8.02 (2H, d, J=8.8 Hz), 7.82 (1H, d, J=8.8 Hz), 7.55 (1H,s), 7.53 (2H, d, J=8.8 Hz), 7.35 (1H, dd, J=8.8, 2.5 Hz), 7.03 (1H, d,J=2.5 Hz), 6.43 (1H, brs), 5.93-5.86 (1H, br), 4.75 (2H, s), 4.22-4.12(4H, m), 1.28 (3H, t, J=7.1 Hz)

MS: 512 (M+H)⁺

Example 279ethyl4-chloro-2-({1-[(4-chlorophenyl)sulfonyl]-3,7-dioxo-1,4-diazepan-6-yl}methyl)phenylcarbamate(compound 279)

Instead of the starting material of Example 29, that is, the compound 1,the compound of Example 278 was used for the similar procedure as inExample 29 to obtain the title compound.

NMR (CDCl₃): δ7.93 (2H, d, J=8.6 Hz), 7.55-7.48 (1H, br), 7.49 (2H, d,J=8.6 Hz), 7.28 (1H, d, J=8.7 Hz), 7.21 (1H, dd, J=8.7, 2.4 Hz), 7.08(1H, d, J=2.4 Hz), 5.83-5.79 (1H, br), 5.01 (1H, d, J=17.7 Hz), 4.43(1H, d, J=17.7 Hz), 4.22 (2H, q, J=7.1 Hz), 3.51-3.40 (2H, m), 3.25 (1H,t, J=11.6 Hz), 3.10 (1H, dd, J=14.6, 7.8 Hz), 2.49 (1H, dd, J=14.5, 5.2Hz), 1.33 (3H, t, J=7.1 Hz)

MS: 514 (M+H)⁺

Example 280 methyl2-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}phenylcarbamate(compound 280)

Instead of the material of Example 278, that is, the compound 204, thecompound S134 was used, while instead of ethyl chlorocarbonate, methylchlorocarbonate was used for the similar procedure as in Example 278 toobtain the title compound.

NMR (DMSO-d₆): δ9.47 (1H, s), 8.24 (1H, d, J=2.2 Hz), 7.85 (1H, br),7.76 (1H, d, J=8.5 Hz), 7.66 (1H, dd, J=8.5, 2.2 Hz), 7.28-7.23 (2H, m),6.97 (1H, d, J=8.5 Hz), 4.87 (1H, d, J=17.4 Hz), 4.5 (1H, d, J=17.4 Hz),3.75 (3H, s), 3.72 (3H, s), 3.70-3.62 (1H, m), 3.33-3.29 (1H, m),3.04-2.94 (2H, m), 2.84 (1H, dd, J=14.2, 4.6 Hz)

MS: 530 (M+H)⁺

Example 2814-[(3-amino-4-chlorophenyl)sulfonyl]-6-(5-chloro-2-methoxybenzyl)-N-ethyl-2,5-dioxo-1,4-diazepan-1-carboxamide(compound 281)

To the compound S134 (52 mg) in tetrahydrofuran (0.5 ml) solution, ethylisocyanate (40 μl) was added under heating and reflux in two additionsand the mixture was stirred for 21 hours. The reaction system wasconcentrated, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate-3/1). The purified product wasagain purified by silica gel column chromatography (hexane/ethylacetate=1/1→2/3). The purified product was recrystallized fromchloroform/hexane to obtain the title compound (15.6 mg).

NMR (CDCl₃): δ8.64 (1H, br), 7.41 (1H, d, J=2.3 Hz), 7.37 (1H, d, J=8.3Hz), 7.23 (1H, dd, J=8.3, 2.3 Hz), 7.18 (1H, dd, J=8.7, 2.5 Hz), 7.06(1H, d, J=2.5 Hz), 6.77 (1H, d, J=8.7 Hz), 4.82 (1H, d, J=16.1 Hz), 4.61(1H, d, J=16.1 Hz), 4.41-4.32 (3H, m), 3.79 (3H, s), 3.50 (1H, dd,J=15.6, 11.5 Hz), 3.35-3.21 (3H, m), 3.12 (1H, dd, J=13.8, 5.6 Hz), 2.94(1H, dd, J=13.8, 7.2 Hz), 1.16 (3H, t, J=7.3 Hz)

MS: 543 (M+H)⁺

Example 282N-(2-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}phenyl)acetoamide(compound 282)

A mixed solution of the compound S134 (300 mg), anhydrous acetic acid (2ml), and pyridine (2 ml) was stirred at room temperature for 18 hours.The reaction solution was concentrated, the residue was purified bysilica gel column chromatography (hexane/ethyl acetate=1/3 to 0/1), andthe purified product was recrystallized from hexane/ethyl acetate toobtain the title compound (170 mg).

NMR (CDCl₃): δ8.73 (1H, d, J=1.9 Hz), 7.80 (1H, dd, J=8.6, 1.9 Hz), 7.64(1H, brs), 7.57 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=8.8, 2.7 Hz), 7.00(1H, d, J=2.7 Hz), 6.77 (1H, d, J=8.8 Hz), 5.98-5.00 (1H, br), 5.04 (1H,d, J=17.8 Hz), 4.44 (1H, d, J=17.8 Hz), 3.80 (3H, s), 3.53-3.55 (1H, m),3.31-3.20 (2H, m), 3.11 (1H, dd, J=14.0, 4.7 Hz), 2.46 (1H, dd, J=14.0,9.0 Hz), 2.26 (3H, s)

MS: 514 (M+H)⁺

Example 283N-(5-{([6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-2-methoxyphenyl)acetoamide(compound 283)

Instead of the starting material of Example 282, that is, the compoundS134, the compound 250 was used for the similar procedure as in Example282 to obtain the title compound.

NMR (DMSO-d₆): δ9.43 (1H, s), 8.60 (1H, m), 7.81 (1H, br), 7.64 (1H, dd,8.7, 2.4 Hz), 7.27-7.23 (3H, m), 6.97 (1H, d, 8.4 Hz), 4.83 (1H, d, 17.5Hz), 4.49 (1H, d, 17.5 Hz), 3.94 (3H, s), 3.74 (3H, s), 3.69-3.59 (1H,m), 3.01-2.91 (2H, m), 2.82 (1H, dd, 14.3, 4.6 Hz), 2.59-2.45 (1H, m),2.12 (3H, s)

MS: 510 (M+H)⁺

Example 284N-(5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}-2-methylphenyl)acetoamide(compound 284)

Instead of the starting material of Example 282, that is, the compoundS134, the compound 200 was used for the similar procedure as in Example282 to obtain the title compound.

NMR (DMSO-d₆): δ9.52 (1H, s), 8.08 (1H, m), 7.83 (1H, br), 7.57 (1H, dd,8.1, 1.7 Hz), 7.46 (1H, d, 8.1 Hz), 7.27-7.23 (2H, m), 6.97 (1H, d, 9.1Hz), 4.85 (1H, d, 17.5 Hz), 4.50 (1H, d, 17.5 Hz), 3.74 (3H, s),3.70-3.61 (1H, m), 3.03-2.93 (2H, m), 2.82 (1H, dd, 14.3, 4.7 Hz),2.54-2.47 (1H, m), 2.30 (3H, s), 2.11 (9H, s)

MS: 494 (M+H)⁺

Example 285N-[3-(acetylamino)phenyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 285)

Instead of the starting material of Example 282, that is, the compoundS134, the compound 171 was used for the similar procedure as in Example282 to obtain the title compound.

NMR (CDCl₃): δ11.22 (1H, s), 7.72 (1H, s), 7.46 (1H, d, J=7.7 Hz),7.35-7.20 (3H, m), 7.19-7.13 (2H, m), 6.82 (1H, d, J=8.7 Hz), 5.86 (1H,br), 5.44 (1H, d, J=17.6 Hz), 4.20 (1H, d, J=17.6 Hz), 3.85 (3H, s),3.83-3.72 (1H, m), 3.40-3.35 (2H, m), 3.22 (1H, dd, J=13.8, 5.4 Hz),2.64 (1H, dd, J=13.8, 7.9 Hz), 2.17 (3H, s)

MS: 459 (M+H)⁺

Melting point: 130-131° C.

Example 286N-[4-(acetylamino)phenyl]-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 286)

Instead of the starting material of Example 282, that is, the compoundS134, the compound 172 was used for the similar procedure as in Example282 to obtain the title compound.

NMR (DMSO-d₆): δ10.97 (1H, s), 9.89 (1H, s), 7.72 (1H, d, J=3.7 Hz),7.52 (2H, d, J=9.0 Hz), 7.42 (2H, d, J=9.0 Hz), 7.35 (1H, d, J=2.6 Hz),7.26 (1H, dd, J=8.9, 2.6 Hz), 7.00 (1H, d, J=8.9 Hz), 4.80 (1H, d,J=17.3 Hz), 4.60 (1H, d, J=17.3 Hz), 3.99-3.89 (1H, m), 3.79 (3H, s),3.21 (1H, t, J=12.7 Hz), 3.08-2.96 (2H, m), 2.66 (1H, dd, J=14.1, 9.1Hz), 2.01 (3H, s)

MS: 459 (M+H)⁺

Example 287N-{1-[4-(acetylamino)phenyl]propyl}-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 287) (diastereomer of compound 288)

Instead of the starting material of Example 282, that is, the compoundS134, the compound 122 was used for the similar procedure as in Example282 to obtain the title compound.

NMR (CDCl₃): δ9.43 (1H, d, J=7.8 Hz), 7.45 (2H, d, J=8.3 Hz), 7.28-7.13(4H, m), 7.11 (1H, d, J=2.6 Hz), 6.80 (1H, d, J=8.7 Hz), 5.70 (1H, brs),5.36 (1H, d, J=17.6 Hz), 4.75 (1H, dd, J=14.4, 7.1 Hz), 4.10 (1H, d,J=17.6 Hz), 3.82 (3H, s), 3.72-3.61 (1H, m), 3.31-3.22 (2H, m), 3.18(1H, dd, J=14.0, 5.2 Hz), 2.59 (1H, dd, J=14.0, 8.4 Hz), 2.16 (3H, s),1.90-1.74 (2H, m), 0.88 (3H, t, J=7.3 Hz)

MS: 501 (M+H)⁺

Example 288N-[1-{4-(acetylamino)phenyl]propyl}-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 288) (diastereomer of compound 287)

Instead of the starting material of Example 282, that is, the compoundS134, the compound 123 was used for the similar procedure as in Example282 to obtain the title compound.

NMR (CDCl₃): δ9.44 (1H, d, J=7.7 Hz), 7.44 (2H, d, J=8.3 Hz), 7.27-7.17(3H, m), 7.11 (1H, d, J=2.5 Hz), 7.13-7.04 (1H, br), 6.79 (1H, d, J=8.8Hz), 5.59 (1H, brs), 5.36 (1H, d, J=17.4 Hz), 4.73 (1H, dd, J=14.4, 7.1Hz), 4.05 (1H, d, J=17.4 Hz), 3.81 (3H, s), 3.72-3.61 (1H, m), 3.36-3.27(2H, m), 3.18 (1H, dd, J=14.0, 5.0 Hz), 2.59 (1H, dd, J=14.0, 8.6 Hz),2.16 (3H, s), 1.93-1.75 (2H, m), 0.90 (3H, t, J=7.3 Hz)

MS: 501 (M+H)⁺

Example 289N-(2-chloro-5-{[6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]sulfonyl}phenyl)methanesulfonamide (compound 289)

To the compound 90 (51 mg) in pyridine (0.5 ml) solution,methanesulfonyl chloride (10 μM) was added under ice cooling and themixture was stirred at room temperature for 1 hour. The reactionsolution was diluted with ethyl acetate, then the mixture wassuccessively washed with saturated potassium hydrogensulfate aqueoussolution and saturated saline, dried over with anhydrous sodium sulfate,then concentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1) to obtain the title compound(1.7 mg).

NMR (CDCl₃): δ7.99 (1H, d, J=2.1 Hz), 7.80 (1H, dd, J=8.5, 2.1 Hz), 7.61(1H, d, J=8.5 Hz), 7.18 (1H, dd, J=8.7, 2.6 Hz), 7.04-6.96 (1H, br),7.01 (1H, d, J=2.6 Hz), 6.77 (1H, d, J=8.7 Hz), 5.77 (1H, br), 4.99 (1H,d, J=17.7 Hz), 4.43 (1H, d, J=17.7 Hz), 3.80 (3H, s), 3.55-3.48 (2H, m),3.25-3.18 (1H, m), 3.22 (3H, s), 3.09 (1H, dd, J=13.9, 5.0 Hz), 2.51(1H, dd, J=13.9, 8.7 Hz)

MS: 550 (M+H)⁺

Example 2906-(5-chloro-2-methoxybenzyl)-N-(1-{4-[(methylsulfonyl)amino]phenyl}propyl)-3,7-dioxo-1,4-diazepan-1-carboxamide(compound 290)

Instead of the starting material of Example 289, that is, the compound90, the compound 123 was used for the similar procedure as in Example289 to obtain the title compound.

NMR (CDCl₃): δ9.48 (1H, d, J=7.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.22 (1H,dd, J=8.7, 2.6 Hz), 7.17 (2H, d, J=8.4 Hz), 7.14 (1H, d, J=2.6 Hz), 6.81(1H, d, J=8.7 Hz), 6.37 (1H, s), 5.67 (1H, brs), 5.35 (1H, d, J=17.6Hz), 4.76 (1H, dd, J=14.4, 7.1 Hz), 4.08 (1H, d, J=17.6 Hz), 3.83 (3H,s), 3.71-3.63 (1H, m), 3.37-3.30 (2H, m), 3.19 (1H, dd, J=14.0, 5.4 Hz),3.00 (3H, s), 2.63 (1H, dd, J=14.0, 8.2 Hz), 1.90-1.75 (2H, m), 0.93(3H, t, J=7.3 Hz)

MS: 537 (M+H)⁺

Reference Example 177(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(5-fluoro-2-methoxyphenyl)-2-propenoicacid (compound S177)

Instead of the ingredient in Reference Example 2, that is, the compoundS1, 5-fluoro-2-methoxybenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

Reference Example 178(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(3-pyridyl)-2-propenoicacid (compound S178)

Instead of the starting material in Reference Example 2, that is, thecompound S1, nicotine aldehyde was used for the similar procedure as inReference Example 2 to Reference Example 5 and Reference Example 23 toobtain the title compound.

Reference Example 179(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(4-pyridyl)-2-propenoicacid (compound S179)

Instead of the starting material in Reference Example 2, that is, thecompound S1, isonicotine aldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 5 and Reference Example 23to obtain the title compound.

Reference Example 180(2E)-2-{[(tert-butoxycarbonyl)amino]methyl}-3-(6-fluoro-2-methoxyphenyl)-2-propenoicacid (compound S180)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 5-fluoro-2-methoxybenzaldehyde was used for the similarprocedure as in Reference Example 2 to Reference Example 5 and ReferenceExample 23 to obtain the title compound.

NMR (CDCl₃): δ7.75-7.45 (1H, m), 7.35-7.21 (1H, m), 6.80-6.68 (2H, m),3.97 (2H, d, J=6.0 Hz), 3.86 (3H, s), 1.50-1.05 (9H, m)

Reference Example 181(2E)-3-(4,5-dichloro-2-methoxyphenyl)-2-[[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S181)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 4,5-dichloro-2-methoxybenzaldehyde was used for the similarprocedure as in Reference Example 2 to Reference Example 6 to obtain thetitle compound.

NMR (CDCl₃): δ7.96 (1H, s), 7.57 (1H, s), 7.15-6.95 (2H, m), 4.33 (2H,d, J=6.1 Hz), 3.86 (3H, s)

Reference Example 182(2E)-3-(3,5-difluoro-2-methoxyphenyl)-2-[[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S182)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 3,5-difluoro-2-methoxybenzaldehyde was used forsuccessively the similar procedures as in Reference Example 2 toReference Example 6 to obtain the title compound.

NMR (CDCl₃): δ7.99 (1H, s), 7.08 (1H, br), 7.05-7.00 (1H, m), 6.99-6.90(1H, m), 4.33 (2H, d, J=6.2 Hz), 3.89 (3H, s)

Reference Example 183(2E)-3-(2-fluorophenyl)-2-[[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S183)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 2-fluorobenzaldehyde was used for the similar procedure asin Reference Example 2 to Reference Example 6 to obtain the titlecompound.

Reference Example 184(2E)-3-(5-chloro-4-fluoro-2-methoxyphenyl)-2-[[(trifluoroacetyl)amino]methyl}-2-propenoicacid (compound S184)

Instead of the starting material in Reference Example 2, that is, thecompound S1, 5-chloro-4-fluoro-2-methoxybenzaldehyde was used for thesimilar procedure as in Reference Example 2 to Reference Example 6 toobtain the title compound.

NMR (CDCl₃): δ7.96 (1H, s), 7.55 (1H, d, J=8.2 Hz), 7.06 (1H, br), 6.77(1H, d, J=10.6 Hz), 4.34 (2H, d, J=6.0 Hz), 3.85 (3H, s)

Reference Example 185(2Z)-2-{[(tert-butoxycarbonyl)amino]ethyl}-3-(2-isopropoxy-5-chlorophenyl)-2-propenoicacid (compound S185)

Instead of the n-butyl iodide of Reference Example 53, i-propyl iodidewas used for the similar procedure as in Reference Example 53 to obtainthe title compound.

Example 2914-[(4-chlorophenyl)sulfonyl]-6-(3-pyridinylmethyl)-1,4-diazepan-2,5-dione(compound 291)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S178 was used for the similar procedure as inReference Example 119, Reference Example 120, Reference Example 124,Example 1, and Example 29 to obtain the title compound.

NMR (DMSO-d₆): δ8.44 (1H, s), 8.4 (1H, d, J=4.7 Hz), 7.93 (2H, d, J=8.5Hz), 7.86 (1H, br), 7.73 (2H, d, J=8.5 Hz), 7.63 (1H, d, J=7.9 Hz), 7.29(1H, dd, J=7.9, 4.7 Hz), 4.9 (1H, d, J=17.6 Hz), 4.53 (1H, d, J=17.6Hz), 3.88-3.74 (1H, m), 3.10-2.89 (3H, m), 2.60-2.47 (1H, m)

MS: 394 (M+H)⁺

Example 2924-[(4-chlorophenyl)sulfonyl]-6-(4-pyridinylmethyl)-1,4-diazepan-2,5-dione(compound 292)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S179 was used for the similar procedure as inReference Example 119, Reference Example 120, Reference Example 124,Example 1, and Example 29 to obtain the title compound.

NMR (DMSO-d₆): δ8.44 (2H, d, J=5.3 Hz), 7.92 (2H, d, J=8.6 Hz), 7.87(1H, br), 7.73 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=5.3 Hz), 4.92 (1H, d,J=17.6 Hz), 4.54 (1H, d, J=17.6 Hz), 3.90-3.79 (1H, m), 3.09-2.90 (3H,m), 2.65-2.46 (1H, m)

MS: 394 (M+H)⁺

Example 2936-(5-chloro-2-isopropoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 293)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S185 was used for the similar procedure as inReference Example 119, Reference Example 120, Reference Example 124,Example 1, and Example 29 to obtain the title compound.

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.15 (1H,dd, J=8.8, 2.6 Hz), 7.02 (1H, d, J=2.6 Hz), 6.76 (1H, d, J=8.8 Hz), 5.69(1H, br), 5.01 (1H, d, J=17.6 Hz), 4.58-4.48 (1H, m), 4.35 (1H, d,J=17.6 Hz), 3.53-3.43 (1H, m), 3.23 (1H, dt, J=13.0, 4.2 Hz), 3.14 (1H,d, J=13.0 Hz), 3.07 (1H, dd, J=14.2, 4.8 Hz), 2.54 (1H, dd, J=14.2, 9.1Hz), 1.29 (6H, d, J=6.0 Hz)

MS: 485 (M+H)⁺

Example 2944-[(4-chlorophenyl)sulfonyl]-6-(4,5-dichloro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 294)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S181 was used for the similar procedure as inReference Example 117, Reference Example 122, Example 1, and Example 29to obtain the title compound.

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.12 (1H,s), 6.93 (1H, s), 5.7 (1H, br), 5 (1H, d, J=17.7 Hz), 4.39 (1H, d,J=17.7 Hz), 3.81 (3H, s), 3.49-3.38 (1H, m), 3.22 (1H, dt, J=11.7, 4.4Hz), 3.16 (1H, d, J=11.7 Hz), 3.08 (1H, dd, J=14.2, 5.2 Hz), 2.53 (1H,dd, J=14.2, 8.6 Hz)

MS: 493 (M+H)⁺

Example 2954-[(4-chlorophenyl)sulfonyl]-6-(3,5-difluoro-2-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 295)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S182 was used for the similar procedure as inReference Example 117, Reference Example 122, Example 1, and Example 29to obtain the title compound.

NMR (CDCl₃): δ7.95 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 6.80-6.71(1H, m), 6.65-6.59 (1H, m), 5.71 (1H, br), 5 (1H, d, J=17.6 Hz), 4.4(1H, d, J=17.6 Hz), 3.85 (3H, s), 3.48-3.36 (1H, m), 3.24 (1H, dt,J=13.2, 4.4 Hz), 3.16 (1H, d, J=13.2 Hz), 3.09 (1H, dd, J=14.1, 5.1 Hz),2.61 (1H, dd, J=14.1, 8.7 Hz)

MS: 459 (M+H)⁺

Example 2964-[(4-chlorophenyl)sulfonyl]-6-(2-fluorobenzyl)-1,4-diazepan-2,5-dione(compound 296)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S183 was used for the similar procedure as inReference Example 117, Reference Example 122, Example 1, and Example 29to obtain the title compound.

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.29-7.21(1H, m), 7.19-6.99 (3H, m), 5.8 (1H, br), 5 (1H, d, J=17.7 Hz), 4.42(1H, d, J=17.7 Hz), 3.48-3.35 (1H, m), 3.32-3.12 (3H, m), 2.66 (1H, dd,J=14.4, 8.9 Hz)

MS: 411 (M+H)⁺

Example 2976-(5-chloro-4-fluoro-2-methoxybenzyl)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione(compound 297)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S184 was used for the similar procedure as inReference Example 117, Reference Example 122, Example 1, and Example 29to obtain the title compound.

NMR (CDCl₃): δ7.96 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.07 (1H,d, J=8.3 Hz), 6.68 (1H, d, J=10.7 Hz), 5.68 (1H, br), 5.01 (1H, d,J=17.7 Hz), 4.39 (1H, d, J=17.7 Hz), 3.08 (3H, s), 3.48-3.35 (1H, m),3.23 (1H, dt, J=13.2, 4.0 Hz), 3.15 (1H, d, J=13.2 Hz), 3.08 (1H, dd,J=14.3, 5.3 Hz), 2.52 (1H, dd, J=14.3, 8.6 Hz)

MS: 475 (M+H)⁺

Example 2984-[(4-chlorophenyl)sulfonyl]-6-(2-fluoro-6-methoxybenzyl)-1,4-diazepan-2,5-dione(compound 298)

Instead of the starting material of Reference Example 119, that is, thecompound S26, the compound S180 was used for the similar procedure as inReference Example 119, Reference Example 120, Reference Example 124,Example 1, and Example 29 to obtain the title compound.

NMR (CDCl₃): δ7.99 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.21 (1H,dd, J=8.4, 7.0 Hz), 6.71-6.64 (2H, m), 5.62 (1H, br), 5.02 (1H, d,J=17.6 Hz), 4.41 (1H, d, J=17.6 Hz), 3.82 (3H, s), 3.46-3.35 (1H, m),3.25-3.10 (2H, m), 3.09-3.00 (1H, m), 2.82 (1H, dd, J=14.1, 10.9 Hz)

MS: 441 (M+H)⁺

Reference Example 186 tert-butyl[4-(1-aminopropyl)phenyl]acetatehydrochloride (compound S186)

To tert-butyl(4-propionylphenyl)acetate (1 g) in ethanol (20 ml)solution, sodium acetate (0.7 g) and hydroxylamine hydrochloride (0.44g) were added and the mixture was stirred at 90° C. for 3 hours.Distilled water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. Ethanol (22 ml) and 10% palladium carbon (0.6 g) wereadded to the residue, and the mixture was stirred under hydrogenatmosphere at 5 atm for 40 hours. The insoluble compound was filteredout, then a 4N hydrochloric acid/ethyl acetate solution was added to thefiltrate and the mixture concentrated. Hexane/ethyl acetate was added tothe residue, and the precipitated solid was collected by filtration toobtain the title compound (0.74 g).

NMR (DMSO-d6): δ8.34 (2H, br), 7.4 (2H, d, J=8.1 Hz), 7.3 (2H, d, J=8.1Hz), 4.1 (1H, dd, J=9.0, 5.6 Hz), 3.58 (2H, s), 2.01-1.72 (2H, m), 1.39(9H, s), 0.75 (3H, t, J=7.4 Hz)

Example 299{4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]phenyl}aceticacid (compound 299) (diastereomer of Compound 300)

The compound S141C was used instead of the starting material compound ofReference Example 142A, that is, the compound S141A, and the compoundS186 was used instead of the starting material compound of ReferenceExample 142A, that is, the compound S83, for the similar procedure as inReference Example 142A and Example 91 to obtain the title compound.

NMR (DMSO-d6): δ9.45 (1H, d, J=7.5 Hz), 7.68 (1H, br), 7.33 (1H, d,J=2.4 Hz), 7.30-7.18 (5H, m), 7 (1H, d, J=8.8 Hz), 4.75 (1H, d, J=17.3Hz), 4.66 (1H, q, J=7.5 Hz), 4.47 (1H, d, J=17.3 Hz), 3.90-3.81 (1H, m),3.78 (3H, s), 3.54 (2H, s), 3.15 (1H, t, J=13.0 Hz), 3.06-2.92 (2H, m),2.70-2.62 (1H, m), 1.86-1.70 (2H, m), 0.83 (3H, t, J=7.3 Hz)

MS: 502 (M+H)⁺

Example 300{4-[(1S)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]phenyl}aceticacid (compound 300) (diastereomer of Compound 299)

The compound S141B was used instead of the starting material compound ofReference Example 142A, that is, the compound S141A, and the compoundS186 was used instead of the starting material compound of ReferenceExample 142A, that is, the compound S83, for the similar procedure as inReference Example 142A and Example 91 to obtain the title compound.

NMR (DMSO-d6): δ9.42 (1H, d, J=7.7 Hz), 7.66 (1H, br), 7.33 (1H, d,J=2.7 Hz), 7.30-7.19 (5H, m), 7.01 (1H, d, J=8.8 Hz), 4.76 (1H, d,J=17.4 Hz), 4.67 (1H, q, J=7.7 Hz), 4.52 (1H, d, J=17.4 Hz), 3.93-3.82(1H, m), 3.79 (3H, s), 3.54 (2H, s), 3.13 (1H, t, J=13.0 Hz), 3.04-2.92(2H, m), 2.70-2.60 (1H, m), 1.86-1.70 (2H, m), 0.82 (3H, t, J=7.3 Hz)

MS: 502 (M+H)⁺

Example 3013-[(1R)-1-({[(6R)-6-(2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 301)

To the compound 91 (100 mg) in tetrahydrofuran (2 ml) solution, a 10%palladium carbon catalyst (100 mg) was added and the mixture was stirredat a 5 kgf/cm² hydrogen atmosphere at room temperature for 36 hours. Thereaction was incomplete, so the reaction was stopped once, the catalystwas filtered, and the residue was washed with ethyl acetate. Thefiltrate and the washings were combined, successively washed withsaturated ammonium chloride aqueous solution, water, and saturatedsaline, dried over with anhydrous sodium sulfate, then concentrated. Theresidue was dissolved in tetrahydrofuran (2 ml), 10% palladium carboncatalyst (100 mg) was added, and the mixture was again stirred in 5kgf/cm² hydrogen atmosphere at room temperature for 18 hours. The end ofthe reaction was confirmed, then the catalyst was filtered, and theresidue was washed with ethyl acetate. The filtrate and the washingswere combined, successively washed with saturated ammonium chlorideaqueous solution, water, and saturated saline, dried over with anhydroussodium sulfate, then concentrated. The residue was crystallized fromethyl acetate/hexane to obtain the title compound (63.9 mg).

NMR (DMSO-d₆): δ9.52 (1H, d, J=7.4 Hz), 7.87 (1H, s), 7.83 (1H, d, J=7.7Hz), 7.71 (1H, d, J=3.6 Hz), 7.57 (1H, d, J=7.7 Hz), 7.47 (1H, dd,J=7.7, 7.7 Hz), 7.25-7.21 (2H, m), 6.98 (1H, d, J=8.2 Hz), 6.90 (1H, dd,J=7.3, 7.3 Hz), 4.75 (1H, dt, J=7.4, 7.4 Hz), 4.74 (1H, d, J=17.1 Hz),4.47 (1H, d, J=17.1 Hz), 3.83 (1H, m), 3.79 (3H, s), 3.17 (1H, dd,J=12.7, 12.7 Hz), 3.02 (1H, m), 3.01 (1H, dd, J=14.4, 4.8 Hz), 2.65 (1H,dd, J=14.4, 9.2 Hz), 1.86-1.76 (2H, m), 0.85 (3H, t, J=7.4 Hz)

MS: 454 (M+H)⁺

Example 3022-amino-4-[(1R)-1-({[(6R)-6-(2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 302)

Instead of the starting material of Example 301, that is, the compound91, the compound 178B was used for the similar procedure as in Example301. The obtained crude product was crystallized from ethylacetate/hexane to obtain the title compound.

NMR (DMSO-d₆): δ9.45 (1H, d, J=7.6 Hz), 7.71 (1H, d, J=4.2 Hz), 7.65(1H, d, J=8.3 Hz), 7.25-7.21 (2H, m), 6.99 (1H, d, J=8.9 Hz), 6.90 (1H,dd, J=7.9, 7.9 Hz), 6.63 (1H, d, J=1.5 Hz), 6.44 (1H, dd, J=8.3, 1.5Hz), 4.77 (1H, d, J=17.2 Hz), 4.54 (1H, dt, J=7.6, 7.1 Hz), 4.49 (1H, d,J=17.2 Hz), 3.84 (1H, m), 3.79 (3H, s), 3.19 (1H, m), 3.16 (1H, dd,J=12.7, 12.7 Hz), 3.00 (1H, dd, J=14.4, 4.5 Hz), 2.64 (1H, dd, J=14.4,8.9 Hz), 1.78-1.72 (2H, m), 0.84 (3H, t, J=7.3 Hz)

MS: 469 (M+H)⁺

Example 3032-amino-4-[(1R)-1-({[(6S)-6-(2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid acetate solvate (compound 303)

Instead of the starting material of Example 301, that is, the compound91, the compound 179B was used for the similar procedure as in Example301. The obtained crude product was crystallized from acetic acid toobtain the title compound.

NMR (DMSO-d₆): δ9.44 (1H, d, J=7.4 Hz), 7.69 (1H, J=3.9 Hz), 7.66 (1H,d, J=8.3 Hz), 7.25-7.21 (2H, m), 6.99 (1H, d, J=8.4 Hz), 6.90 (1H, ddd,J=7.3, 7.3, 1.3 Hz), 6.63 (1H, d, J=1.5 Hz), 6.45 (1H, dd, J=8.3, 1.5Hz), 4.79 (1H, d, J=17.2 Hz), 4.56 (1H, dt, J=7.9, 7.9 Hz), 4.51 (1H, d,J=17.2 Hz), 3.84 (1H, m), 3.79 (3H, s), 3.14 (1H, dd, J=12.6, 12.6 Hz),3.02 (1H, m), 3.01 (1H, dd, J=14.4, 4.4 Hz), 2.64 (1H, dd, J=14.4, 9.2Hz), 1.91 (3H, s), 1.77-1.72 (2H, m), 0.83 (3H, t, J=7.3 Hz)

MS: 469 (M+H)⁺

Reference Example 1872-chlorophenyl(6E)-6-(5-chloro-2-methoxybenzylidene)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate(compound S187)

The compound S139 was used instead of the starting material compound ofReference Example 141A, that is, the compound S140A, for the similarprocedure as in Reference Example 141A to obtain the title compound.

NMR (CDCl₃): δ7.68 (1H, s), 7.44 (1H, dd, J=7.8, 1.3 Hz), 7.35-7.18 (4H,m), 7.01 (1H, d, J=2.5 Hz), 6.83 (1H, d, J=8.7 Hz), 5.9 (2H, s), 4.76(2H, s), 4.73 (2H, s), 4.04 (2H, s), 3.82 (3H, s), 3.79 (3H, s), 3.64(6H, s)

Example 3042-amino-4-[(1R)-1-({[(6E)-6-(5-chloro-2-methoxybenzylidene)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoicacid (compound 304)

The compound S187 was used instead of the starting material compound ofReference Example 142A, that is, the compound S141A, and the compoundS101 was used instead of the starting material compound of ReferenceExample 142A, that is, the compound S83, for the similar procedure as inReference Example 142A and Example 91 to obtain the title compound.

NMR (DMSO-d6): δ9.34 (1H, d, J=7.8 Hz), 7.66 (1H, br), 7.46 (1H, d,J=8.3 Hz), 7.33 (1H, s), 7.28 (1H, dd, J=8.8, 2.6 Hz), 7.18 (1H, d,J=2.6 Hz), 6.94 (1H, d, J=8.8 Hz), 6.45 (1H, s), 6.26 (1H, d, J=8.3 Hz),4.38 (1H, q, J=7.8 Hz), 4.33 (2H, s), 4.05-4.00 (2H, m), 3.64 (3H, s),1.63-1.50 (2H, m), 0.96 (3H, t, J=7.2 Hz)

MS: 501 (M+H)⁺

Example 3054-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-nitrobenzoicacid (compound 304)

The compound S162 was used instead of the starting material of Example179A, that is, the compound S165, for the similar procedure as inExample 179A to obtain the title compound.

NMR (DMSO-d6): δ9.43 (1H, d, J=7.1 Hz), 7.95 (1H, d, J=1.3 Hz), 7.83(1H, d, J=8.0 Hz), 7.73 (1H, dd, J=8.0, 1.3 Hz), 7.67 (1H, d, J=3.7 Hz),7.34 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.8, 2.6 Hz), 7.01 (1H, d, J=8.8Hz), 4.83 (1H, q, J=7.1 Hz), 4.71 (1H, d, J=17.2 Hz), 4.53 (1H, d,J=17.2 Hz), 3.93-3.82 (1H, m), 3.79 (3H, s), 3.15 (1H, t, J=12.9 Hz),3.08-2.95 (2H, m), 2.66 (1H, dd, J=14.3, 9.1 Hz), 1.90-1.75 (2H, m),0.87 (3H, t, J=7.3 Hz)

MS: 533 (M+H)⁺

Reference Example 1881-{4-[(4-methoxybenzyl)sulfanyl]phenyl}-1-propanone (compound S188)

To (4-methoxyphenyl)methane thiol (20 g) in N,N-dimethylformamide (200ml) solution, sodium hydride (60% mineral oil dispersion) was addedunder ice cooling and the mixture was stirred for 10 minutes.4-fluoropropiophenone was added to the reaction solution and the mixturewas stirred at room temperature for 3 hours. 1N sodium hydroxide aqueoussolution was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over with anhydrous sodium sulfate, thenconcentrated. Methanol was added to the residue, and the precipitatedsolid was collected by filtration to obtain the title compound (37.4 g).

NMR (CDCl₃): δ7.84 (2H, d, J=8.2 Hz), 7.3 (2H, d, J=8.2 Hz), 7.27 (2H,d, J=8.9 Hz), 6.84 (2H, d, J=8.9 Hz), 4.16 (2H, s), 3.79 (3H, s),3.00-2.90 (2H, m), 1.25-1.17 (3H, m)

Reference Example 1891-{4-[(4-methoxybenzyl)sulfanyl]phenyl}-1-propanamine hydrochloride(compound S189)

To the compound S188 (5 g) in ethanol (100 ml) solution, sodium acetate(2.1 g) and hydroxylamine hydrochloride (1.3 g) were added and themixture was stirred at 90° C. for 3 hours. Distilled water was added tothe reaction solution, and the precipitated solid was collected byfiltration. To 2.5 g of the solid, acetic acid (25 ml) and zinc (5 g)were added and the mixture was stirred at 80° C. for 1 hour. Theinsoluble compound was filtered out, and the filtrate was concentrated.Ethanol was added to the residue, then the precipitated solid wascollected by filtration. The obtained solid was diluted with ethylacetate, 4M hydrochloric acid/ethyl acetate solution was added, and themixture was stirred at 60° C. This was allowed to cool and theprecipitated solid was collected by filtration to obtain the titlecompound (0.7 g).

NMR (DMSO-d6): δ8.29 (3H, br), 7.41-7.32 (4H, m), 7.28 (2H, d, J=8.7Hz), 6.85 (2H, d, J=8.7 Hz), 4.21 (2H, s), 4.15-4.05 (1H, m), 1.99-1.70(2H, m), 0.74 (3H, t, J=7.4 Hz)

Reference Example 190(6R)-6-(5-chloro-2-methoxybenzyl)-N-((1R)-1-{4-[(4-methoxybenzyl)sulfanyl]phenyl}-1-propyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxamide(compound S190)

The compound S141C was used instead of the starting material compound ofReference Example 142A, that is, the compound S141A, and the compoundS189 was used instead of the starting material compound of ReferenceExample 142A, that is, the compound S83, for the similar procedure as inReference Example 142A to obtain the title compound.

NMR (CDCl₃): δ9.43 (1H, d, J=8.0 Hz), 7.30-7.12 (7H, m), 6.91 (1H, d,J=2.6 Hz), 6.85-6.80 (1H, m), 6.74 (1H, d, J=8.7 Hz), 6.07 (2H, s), 5.31(1H, d, J=17.4 Hz), 4.80-4.72 (2H, m), 4.32 (1H, d, J=13.8 Hz), 4.19(1H, d, J=17.4 Hz), 4.05 (2H, s), 3.83 (3H, s), 3.78 (3H, s), 3.76 (3H,s), 3.7 (6H, s), 3.59-3.45 (2H, m), 3.15-3.09 (1H, m), 3.07-3.00 (2H,m), 2.39 (1H, dd, J=13.8, 9.5 Hz), 1.88-1.75 (2H, m), 0.87 (3H, t, J=7.4Hz)

Reference Example 191(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-N-[(1R)-1-(4-sulfanylphenyl)propyl]-1,4-diazepan-1-carboxamide(compound S191)

To the compound S190 (290 mg), trifluoroacetic acid (5.8 ml), anisole(0.58 ml), and mercury acetate (II) (131 mg) were added and the mixturewas stirred at room temperature for 5 hours. The reaction solution wasconcentrated, and the residue was purified by SH-silica gel columnchromatography (SH Silica: Fuji Silicia

Chemical) (ethyl acetate) and silica gel column chromatography (ethylacetate) to obtain the title compound (117 mg).

NMR (DMSO-d6): δ9.39 (1H, d, J=7.6 Hz), 7.67 (1H, d, J=3.2 Hz),7.37-7.30 (3H, m), 7.26 (1H, dd, J=8.8, 2.6 Hz), 7.09 (2H, d, J=8.2 Hz),6.99 (1H, d, J=8.8 Hz), 4.74 (1H, d, J=17.1 Hz), 4.6 (1H, q, J=7.6 Hz),4.47 (1H, d, J=17.1 Hz), 3.90-3.80 (1H, m), 3.77 (3H, s), 3.14 (1H, t,J=13.0 Hz), 3.05-2.92 (2H, m), 2.70-2.60 (1H, m), 1.80-1.69 (2H, m), 0.8(3H, t, J=7.0 Hz)

Example 3064-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzenesulfonicacid (compound 306)

To the compound S191 (110 mg) in acetic acid 1.1 (1.1 ml) solution, a32% by weight peracetic acid/acetic acid solution (0.22 ml) was addedand the mixture was stirred at room temperature for 2 hours. Thereaction solution was concentrated, then acetone was added to theresidue. The precipitated solid was collected by filtration to obtainthe title compound (94 mg).

NMR (DMSO-d6): δ9.46 (1H, d, J=7.5 Hz), 7.68 (1H, br), 7.54 (2H, d,J=8.2 Hz), 7.33 (1H, d, J=2.6 Hz), 7.27 (1H, dd, J=8.8, 2.6 Hz), 7.22(2H, d, J=8.2 Hz), 7 (1H, d, J=8.8 Hz), 4.75 (1H, d, J=17.1 Hz), 4.67(1H, q, J=7.5 Hz), 4.47 (1H, d, J=17.1 Hz), 3.92-3.80 (1H, m), 3.78 (3H,s), 3.15 (1H, t, J=13.2 Hz), 3.06-2.92 (2H, m), 2.71-2.64 (1H, m),1.90-1.69 (2H, m), 0.82 (3H, t, J=7.3 Hz)

MS: 524 (M+H)⁺

Reference Example 192({3-[(tert-butoxycarbonyl)amino]-2-hydroxypropanoyl}amino)ethyl acetate(compound S192)

isoserine (454 mg) was dissolved in 2M sodium hydroxide aqueous solution(4 ml) and tetrahydrofuran (8 ml), then di-tert-butyldicarbonate (1 g)was added and the mixture was stirred at room temperature for 1.5 hours.Further, di-tert-butyldicarbonate (0.5 g) was added and the mixture wasstirred at room temperature for 1 hour. To the reaction mixture,N,N-dimethylethylenediamine (0.5 ml) was added, the mixture was stirredat room temperature for 30 minutes, then tetrahydrofuran was distilledoff. Saturated potassium hydrogensulfate aqueous solution was added tothe obtained aqueous mixture to acidify the mixture, then the mixturewas extracted with ethyl acetate. The extract was combined andsuccessively washed with water and saturated saline, dried over withanhydrous sodium sulfate, and concentrated to obtainN-tert-butoxycarbonyl-isoserine as a crude product (829 mg). Theobtained product (829 mg) was dissolved in dichloromethane (10 ml),glycine ethyl ester hydrochloride (850 mg), 1-hydroxybenztriazole (655mg), and triethylamine (0.85 ml) were added to the solution, and themixture was stirred at room temperature for 15 minutes. The reactionmixture was cooled to 0° C., then1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (930 mg) wasadded and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted with ethyl acetate, the mixture wassuccessively washed with water, saturated potassium hydrogensulfateaqueous solution, water, saturated sodium hydrogencarbonate aqueoussolution, and saturated saline, and the organic layer was dried overwith anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=2/1→1/2) to obtain the title compound (441 mg).

NMR (CDCl₆): δ7.46 (1H, br), 5.23 (1H, br.s), 5.22 (1H, br.s), 4.23 (1H,m), 4.22 (2H, q, J=7.1 Hz), 4.11 (1H, dd, J=18.1, 5.1 Hz), 4.00 (1H, dd,J=18.1, 5.4 Hz), 3.63 (1H, ddd, J=14.8, 6.2, 2.9 Hz), 1.45 (9H, s), 1.29(3H, t, J=7.1 Hz)

Reference Example 193({3-[(tert-butoxycarbonyl)amino]-2-[(2-methoxyphenyl)sulfanyl]propanoyl}amino)ethylacetate (compound S193)

(Step 1) The compound S192 (441 mg) was dissolved in pyridine (5 ml),the mixture was cooled to 0° C., then methanesulfonyl chloride (0.18 ml)was added and the mixture was stirred at 0° C. for 45 minutes. Further,methanesulfonyl chloride (0.18 ml) was added and the mixture was stirredat 0° C. for 45 minutes. Water (5 ml) was added and the mixture wasstirred for 15 minutes, then the mixture was extracted with ethylacetate. The extract was combined and successively washed with saturatedpotassium hydrogensulfate aqueous solution, water, and saturated saline,dried over with anhydrous sodium sulfate, and concentrated to obtain({3-[(tert-butoxycarbonyl)amino]-2-[(methylsulfonyl)oxy]propanoyl}amino)ethylacetate as a crude product.

NMR (CDCl₆): δ6.96 (1H, br), 5.10 (1H, dd, J=5.3, 5.3 Hz), 5.09 (1H,br), 4.23 (2H, q, J=7.1 Hz), 4.12 (1H, dd, J=18.1, 5.8 Hz), 4.01 (1H,dd, J=18.1, 5.3 Hz), 3.82 (1H, ddd, J=14.9, 7.1, 5.3 Hz), 3.59 (1H, ddd,J=14.9, 5.3, 5.3 Hz), 3.21 (3H, s), 1.44 (9H, s), 1.30 (3H, t, J=7.1 Hz)

(Step 2) To 2-methoxybenzenethiol (850 mg) in N,N-dimethylformamide (2ml) solution, sodium hydride in 60% mineral oil dispersion (243 mg) awas added at 0° C., then N,N-dimethylformamide (2 ml) was further addedand the temperature raised to room temperature. The({3-[(tert-butoxycarbonyl)amino]-2-[(methylsulfonyl)oxy]propanoyl}amino)ethylacetate obtained as a crude product (397 mg) at step 1 was added to theobtained solution, then the mixture was stirred at room temperature for1.5 hours. Water (10 ml) was added to the reaction mixture and themixture was extracted with a hexane-ethyl acetate (1:1) mixed solvent.The extract was combined and was successively washed with saturatedpotassium hydrogensulfate aqueous solution and saturated saline, driedover with anhydrous sodium sulfate, then concentrated. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=2/1→1/2) to obtain the title compound (400 mg).

NMR (CDCl₆): δ7.48 (1H, d, J=7.3 Hz), 7.31 (1H, ddd, J=8.1, 7.6, 1.6Hz), 7.20 (1H, br), 6.94-6.90 (2H, m), 5.33 (1H, br), 4.23 (2H, q, J=7.2Hz), 4.06 (1H, dd, J=18.4, 5.4 Hz), 4.00 (1H, dd, J=18.4, 5.4 Hz), 3.94(3H, s), 3.80 (1H, m), 3.62-3.56 (2H, m), 1.41 (9H, s), 1.29 (3H, t,J=7.2 Hz)

Reference Example 1946-[(2-methoxyphenyl)sulfanyl]-1-(2,4,6-trimethoxybenzyl)-1,4-diazepan-2,5-dione(compound S194)

Instead of the starting material of Reference Example 136, that is, thecompound S135, the compound S193 was used for the similar procedure asin Examples 136 to 139 to obtain the title compound.

NMR (CDCl₆): δ7.30 (1H, ddd, J=7.6, 7.3, 1.8 Hz), 7.27 (1H, dd, J=7.6,1.8 Hz), 6.86 (1H, ddd, J=7.3, 6.8, 1.8 Hz), 6.83 (1H, dd, J=6.8, 1.8Hz), 6.04 (1H, dd, J=8.0, 4.1 Hz), 4.92 (1H, d, J=13.7 Hz), 4.26 (1H, d,J=13.7 Hz), 4.10 (1H, dd, J=15.4, 4.1 Hz), 3.83 (3H, s), 3.81 (3H, s),3.70 (6H, s), 3.69 (1H, dd, J=15.2, 12.0 Hz), 3.53 (1H, dd, J=15.4, 8.0Hz), 3.45 (1H, dd, J=12.0, 6.4 Hz), 3.32 (1H, dd, J=15.2, 6.4 Hz)

Reference Example 195 tert-butyl4-[(1R)-1-({[6-[(2-methoxyphenyl)sulfanyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]-2-nitrobenzoate(compound S195A) and (compound S195B) (compound 195A and Compound 195Bare diastereomers)

Instead of the starting material of Reference Example 141, that is, thecompound S140, the compound S194 was used for the similar proceddre asin Reference Examples 141 and 142 to obtain the title compound.(compound S195A)

NMR (CDCl₆): δ9.46 (1H, d, J=7.2 Hz), 7.68 (1H, d, J=7.9 Hz), 7.67 (1H,d, J=1.5 Hz), 7.54 (1H, dd, J=8.0, 1.5 Hz), 7.33 (1H, dd, J=7.8, 1.6Hz), 7.36 (1H, ddd, J=8.0, 8.0, 1.6 Hz), 6.90-6.87 (2H, m), 6.07 (2H,s), 4.84 (1H, dt, J=7.3, 7.3 Hz), 4.75 (1H, d, J=16.0 Hz), 4.69 (1H, d,J=13.7 Hz), 4.56 (1H, d, J=16.0 Hz), 4.40 (1H, d, J=13.7 Hz), 4.16 (1H,dd, J=11.2, 7.2 Hz), 3.83 (3H, s), 3.82 (3H, s), 3.65 (6H, s), 3.47 (1H,dd, J=14.9, 11.2 Hz), 3.36 (1H, dd, J=14.9, 7.2 Hz), 1.79 (1H, dq,J=7.4, 7.2 Hz), 1.55 (9H, s), 0.91 (3H, t, J=7.4 Hz) (compound S195B)

NMR (CDCl₆): δ9.46 (1H, d, J=6.6 Hz), 7.70-7.67 (2H, m), 7.51 (1H, d,J=7.9 Hz), 7.35 (1H, ddd, J=7.4, 7.4, 1.3 Hz), 7.31 (1H, dd, J=8.0, 1.3Hz), 6.87-6.83 (2H, m), 6.07 (2H, s), 4.83 (1H, dt, J=7.9, 7.5 Hz), 4.81(1H, d, J=15.8 Hz), 4.68 (1H, d, J=13.7 Hz), 4.46 (1H, d, J=15.8 Hz),4.44 (1H, d, J=13.7 Hz), 4.11 (1H, dd, J=11.0, 7.5 Hz), 3.83 (3H, s),3.77 (3H, s), 3.66 (6H, s), 3.45 (1H, dd, J=15.1, 11.0 Hz), 3.36 (1H,dd, J=15.1, 7.5 Hz), 1.78 (1H, dq, J=7.5, 7.2 Hz), 1.55 (9H, s), 0.91(3H, t, J=7.2 Hz)

Example 3072-amino-4-{(1R)-1-[({6-[(2-methoxyphenyl)sulfanyl]-3,7-dioxo-1,4-diazepan-1-yl]carbonyl)amino]propyl}benzoicacid (compound 307) (diastereomer of Compound 308)

Instead of the starting material of Reference Example 164, that is, thecompound S161, the compound S195A was used for the similar procedure asin Reference Example 164 and Example 178. The obtained crude product waspurified by preparative thin layer chromatography (chloroform/ethylacetate/methanol/acetic acid=10/10/1/0.1 to obtain the title compound.

NMR (DMSO-d₆): δ9.17 (1H, d, J=7.6 Hz), 7.90 (1H, d, J=4.4 Hz), 7.66(1H, d, J=8.0 Hz), 7.44 (1H, dd, J=7.7, 1.5 Hz), 7.33 (1H, ddd, J=7.7,7.7, 1.5 Hz), 7.06 (1H, d, J=8.2 Hz), 6.98 (1H, dd, J=7.6, 7.6 Hz), 6.61(1H, s), 6.43 (1H, d, J=8.2 Hz), 5.19 (1H, dd, J=11.3, 4.4 Hz), 4.73(1H, d, J=17.0 Hz), 4.64 (1H, d, J=17.0 Hz), 4.53 (1H, dt, J=7.3, 7.6Hz), 3.84 (3H, s), 3.47 (1H, m), 3.30 (1H, m), 1.17-1.69 (2H, m), 0.83(3H, t, J=7.3 Hz)

MS: 487 (M+H)⁺

Example 3082-amino-4-{(1R)-1-[({6-[(2-methoxyphenyl)sulfanyl]-3,7-dioxo-1,4-diazepan-1-yl}carbonyl)amino]propyl}benzoicacid (compound 308) (diastereomer of Compound 307)

Instead of the starting material of Reference Example 164, that is, thecompound S161, the compound S195B was used for the similar procedure asin Reference Example 164 and Example 178. The obtained crude product waspurified by preparative thin layer chromatography (chloroform/ethylacetate/methanol/acetic acid=10/10/1/0.1 to obtain the title compound.

NMR (DMSO-d₆): δ9.16 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=4.7 Hz), 7.67(1H, d, J=8.1 Hz), 7.44 (1H, dd, J=7.6, 1.5 Hz), 7.33 (1H, ddd, J=7.8,7.8, 1.5 Hz), 7.06 (1H, d, J=8.2 Hz), 6.97 (1H, dd, J=7.5, 7.5 Hz), 6.60(1H, s), 6.43 (1H, d, J=7.9 Hz), 5.21 (1H, dd, J=11.3, 4.7 Hz), 4.74(1H, d, J=17.3 Hz), 4.66 (1H, d, J=17.3 Hz), 4.54 (1H, dt, J=7.8, 7.6Hz), 3.83 (3H, s), 3.45 (1H, m), 3.25 (1H, m), 1.80-1.71 (2H, m), 0.84(3H, t, J=7.4 Hz)

MS: 487 (M+H)⁺

Test Example 1 Measurement of Inhibitory Activity of Test Compound forHuman Chymase

The inhibitory activity of the compounds of the present invention forrecombinant human chymase was measured by the method of Pasztor et al.(Pasztor et al., Acta. Biol. Hung. 42: 285-95, 1991). That is,recombinant human chymase was diluted to an appropriate concentration bya 50 mM tris-hydrochloride buffer (pH 7.5), 1M sodium chloride, and0.01% (v/v) Triton X-100 to obtain an enzyme solution. A 10 mM dimethylsulfoxide (hereinafter referred to as DMSO) solution ofSuc-Ala-Ala-Pro-Phe-MCA (Peptide Institute) was diluted 20-fold at thetime of use by 50 mM tris-hydrochloride buffer (pH 7.5), 1M sodiumchloride, and 0.01% (v/v) Triton X-100 to obtain the substrate solution.75 μl of the enzyme solution was mixed with 5 μl of the test compound ina DMSO solution, and then incubated for 10 minutes. 20 μl of thesubstrate solution was added to the mixture, and incubated for a further10 minutes at room temperature. The reaction was stopped by adding 50 μlof 30% (v/v) acetic acid. The intensity of the fluorescence (Ex380 nm,Em460 nm) of the fluorescent substance MCA produced by the degradationof the substrate was measured by a fluorescent photometer (FluoroscanII, Labsystems Japan). Simultaneously, 5 of DMSO was added to a reactioninstead of the test compound, and was used as a blank. The inhibitoryactivity for chymase was calculated based on the value of the blank.Further, the rate of inhibition and the 50% inhibition concentration(IC₅₀ value) were calculated. The IC₅₀ values of representativecompounds are shown in Table XII.

TABLE XII Tested compound IC50 value (μM) 1 Compound 4 1.1 2 Compound 150.16 3 Compound 29 0.034 4 Compound 37 0.39 5 Compound 61 0.26 6Compound 67 0.019 7 Compound 90 0.093 8 Compound 91 0.2 9 Compound 1500.16 10 Compound 151 0.38 11 Compound 178A 0.3 12 Compound 179B 0.14 13Compound 214 0.019 14 Compound 239 0.26 15 Compound 263 0.46 16 Compound269 0.024 17 Compound 272 2.4 18 Compound 285 4.7

Test Example 2 Effect of Test Compounds on Dermatitis Model Induced byRepeated Application of Hapten

Dinitrofluorobenzene (hereinafter referred to as “DNFB”) was used ashapten, and dermatitis was induced in accordance with the method ofNagai et al. (Nagai et al., J. Pharmacol. Exp. Ther. 288: 43-50, 1999).That is, dermatitis was induced by repeated application of 12.5 μl of0.15% (v/v) DNFB (Nacalai Tesque) dissolved in a mixture (ratio 1:3) ofacetone (Wako Pure Chemicals) and olive oil (Wako Pure Chemicals) toboth sides of the right ear, total 25 μl, once a week in 8 week oldfemale C3H/HeN mice (Crea Japan). As a control group, acetone:olive oil(1:3) was applied by the same protocol. Ear thickness was measured atevery week before DNFB application and 24, 48 and 72 hours after DNFBapplication by using microgauge (Mitutoyo), and ear edema was evaluatedby the increase in ear thickness compared to the ear thickness beforethe first DNFB application. Six compounds of chymase inhibitor (compound91, compound 178A, compound 150, compound 179B, compound 29, andcompound 90) were used as test compounds. The test compound wassuspended in 0.5% hydroxypropylcellulose in distilled water (hereinafterreferred to as “0.5% HPC-distilled water”) and was administered orallyat doses of 2 and 10 mg/kg once a day, every day from just before thefirst application of hapten to the end of the experiment. Further, as acontrol, 0.5% HPC-distilled water instead of the test compound wasadministered by the same methods. The number of mice used in thisexperiment was seven per group.

Transient skin reaction was induced by DNFB application, and thistransient skin reaction was increased gradually with increasing thenumber of DNFB application. As a result of oral administration of testcompound to this model, each test compound remarkably inhibited thetransient skin reaction. For example, when compound 91, compound 178A,compound 150, compound 179B, compound 29, and compound 90 at a dose of10 mg/kg were administered orally, the inhibition rates of the skinreaction at 24 hours after DNFB application at fifth week were 26.1%,20.0%, 29.9%, 32.8%, 25.1%, and 31.0%, respectively.

INDUSTRIAL APPLICABILITY

The compound (I) or its salt or a solvate thereof of the presentinvention has chymase inhibitory activity and is useful as apharmaceutical for the prevention and/or treatment of bronchial asthma,urticaria, atopic dermatitis, allergic conjunctivitis, rhinitis,rheumatoid arthritis, mastocytosis, scleroderma, heart failure, cardiachypertrophy, congestive heart failure, hypertension, atherosclerosis,myocardial ischemia, myocardial infarction, restenosis after PTCA,restenosis after bypass graft surgery, ischemic peripheral circulatorydisorders, hyperaldosteronism, diabetic retinopathy, diabeticnephropathy, nephritis, glomerulosclerosis, renal insufficiency,psoriasis, solid tumor, postoperative adhesion, glaucoma, and ocularhypertension, and other diseases. Further, according to the method ofproduction of the present invention, the compound (I), or its salt or asolvate thereof can be efficiently produced with a high yield.

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1-24. (canceled)
 25. A compound, or its salt, or a solvate thereof,having the formula (VIa):

wherein R¹, R², and R³ are the same as defined in claim 1, P is the sameas defined in claim 23, X′ indicates methylene, or X′ forms —CH=togetherwith R¹; P′ indicates a protective group selected from the groupconsisting of (1) allyl, (2) allyloxycarbonyl, (3)9-fluorenylmethylcarbonyl, (4) linear or branched C₁ to C₆alkyloxycarbonyl which may optionally be substituted with 1 to 3 halogenatoms, (5) linear or branched C₁ to C₆ alkylcarbonyl which mayoptionally be substituted with 1 to 3 halogen atoms, (6) C₇ to C₁₆aralkyl which may optionally be substituted with 1 to 3 of (i) a halogenatom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv) nitro, (7) C₅to C₁₆ arylcarbonyl which may optionally be substituted with 1 to 3 of(i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv)nitro, (8) C₇ to C₁₆ aralkyloxycarbonyl which may optionally besubstituted with 1 to 3 of (i) a halogen atom, (ii) C₁ to C₆ alkyl,(iii) C₁ to C₆ alkoxy, or (iv) nitro, and (9) C₅ to C₁₆ arylsulfonylwhich may optionally be substituted with 1 to 3 of (i) a halogen atom,(ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, or (iv) nitro, or a hydrogenatom; R²⁰ is (1) a halogen atom, (2) nitro, (3) cyano, (4) C₁ to C₆alkyl which may optionally be substituted with 1 to 3 halogen atoms, (5)hydroxyl, or (6) C₁ to C₆ alkoxy which may be substituted with 1 to 3groups selected from a halogen atom, C₁ to C₆ alkoxy, carboxyl, and C₁to C₆ alkoxycarbonyl; and R²¹, R²², R²³, and R²⁴ are, independently, (1)a halogen atom, (2) nitro, (3) cyano, (4) C₁ to C₆ alkyl which may besubstituted with 1 to 3 halogen atoms, (5) hydroxyl, or (6) C₁ to C₆alkoxy which may optionally be substituted with 1 to 3 groups selectedfrom a halogen atom, C₁ to C₆ alkoxy, carboxyl, and C₁ to C₆alkoxycarbonyl, or a hydrogen atom, except for the following compounds:(1) Compounds, wherein R²⁰ and R²⁴ are chlorine atoms and R²¹, R²², andR²³ are hydrogen atoms, (2) Compounds, wherein R²⁰, R²², and R²⁴ aremethyl and R²¹ and R²³ are hydrogen atoms, and (3) Compounds, whereinR²⁰ is a chlorine atom or bromine atom and R²¹, R²², R²³, and R²⁴ arehydrogen atoms.
 26. A compound, or a salt thereof, having the formula

wherein Ar indicates (1) a C₆ to C₁₄ aromatic hydrocarbon group, (2) a5- to 8-membered aromatic heterocyclic group including 1 to 4 heteroatoms selected from a nitrogen atom, sulfur atom and oxygen atom, otherthan a carbon atom, or (3) a bicyclic or tricyclic aromatic group formedby condensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon ring, wherein the groups (1) to (3) of the above Armay optionally be substituted with any 1 to 5 groups selected from thegroup consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C₁to C₆ alkyl which may optionally be substituted with 1 to 3 halogenatoms, (v) C₂ to C₆ alkenyl which may optionally be substituted with 1to 3 halogen atoms, (vi) C₂ to C₆ alkynyl which may optionally besubstituted with 1 to 3 halogen atoms, (vii) C₃ to C₆ cycloalkyl, (viii)hydroxyl, (ix) C₁ to C₆ alkoxy which may optionally be substituted with1 to 3 groups selected from a halogen atom, mono- or di-C₁ to C₆alkylamino, C₁ to C₆ alkoxy, mono- or di-C₁ to C₆ alkylcarbamoyl, mono-or di-C₇ to C₁₆ aralkylcarbamoyl, mono- or di-C₁ to C₁₀ heteroaryl-C₁ toC₆ alkylcarbamoyl, carboxyl, and C₁ to C₆ alkoxycarbonyl, (x) C₁ to C₅alkylenedioxy, (xi) C₁ to C₆ alkylthio which may optionally besubstituted with 1 to 3 groups selected from a halogen atom, mono- ordi-C₁ to C₆ alkylamino, C₁ to C₆ alkoxy, mono- or di-C₁ to C₆alkylcarbamoyl, mono- or di-C₇ to C₁₆ aralkylcarbamoyl, mono- or di-C₁to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl, carboxyl and C₁ to C₆alkoxy-carbonyl, (xii) amino, (xiii) mono-C₁ to C₆ alkylamino, (xiv)di-C₁ to C₆ alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C₁ toC₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁ to C₆ alkoxycarbonyl,(xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C₁ to C₆ alkylcarbamoyl,(xxii) di-C₁ to C₆ alkylcarbamoyl, (xxiii) 5- to 6-membered cyclicaminocarbonyl, (xxiv) sulfo, (xxv) C₁ to C₆ alkylsulfonyl, (xxvi) C₁ toC₆ alkoxycarbonylamino, (xxvii) C₁ to C₆ alkylcarbonylamino, (xxviii)mono- or di-C₁ to C₆ alkylaminocarbonylamino, (xxix) aminosulfonyl, and(xxx) mono- or di-C₁ to C₆ alkylaminosulfonyl; X indicates (1) a bond,(2) linear or branched C₁ to C₆ alkylene, (3) an oxygen atom, (4) NR¹³,wherein R¹³ indicates a hydrogen atom or a C₁ to C₆ alkyl group, or (5)—S(O)_(m)— wherein m indicates an integer of 0 to 2; R¹ indicates (1) ahydrogen atom, (2) a halogen atom, or (3) C₁ to C₆ alkyl, or R¹ forms—CH═ together with X; R² and R³ are independently (1) a hydrogen atom,(2) a halogen atom, or (3) C₁ to C₆ alkyl; R⁵ and R⁶ are independently(1) a hydrogen atom or (2) C₁ to C₆ alkyl which may optionally besubstituted with a group selected from the group consisting of (i)carboxyl, (ii) C₁ to C₆ alkoxy, (iii) C₁ to C₆ alkoxycarbonyl, (iv) C₆to C₁₂ aryloxycarbonyl, (v) C₁ to C₁₀ heteroaryloxycarbonyl, and (vi)amino; R² and R³ and also R⁵ and R⁶ may independently form a 3- to8-membered ring; and P indicates a protective group selected from thegroup consisting of (1) allyl, (2) allyloxycarbonyl, (3)9-fluorenylmethylcarbonyl, (4) C₁ to C₆ alkyloxycarbonyl which mayoptionally be substituted with 1 to 3 halogen atoms, (5) C₁ to C₆alkylcarbonyl which may optionally be substituted with 1 to 3 halogenatoms, (6) C₇ to C₁₆ aralkyl which may optionally be substituted with 1to 3 groups selected from (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii)C₁ to C₆ alkoxy, and (iv) nitro, (7) C₅ to C₁₆ arylcarbonyl which mayoptionally be substituted with 1 to 3 groups selected from (i) a halogenatom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv) nitro, (8) C₇to C₁₆ aralkyloxycarbonyl which may optionally be substituted with 1 to3 groups selected from (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁to C₆ alkoxy, and (iv) nitro, or (9) C₅ to C₁₆ arylsulfonyl which mayoptionally be substituted with 1 to 3 groups selected from (i) a halogenatom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxyl, and (iv) nitro, orR⁴, wherein R⁴ indicates a (1) a hydrogen atom, (2) C₁ to C₆alkylcarbamoyl, or (3) C₁ to C₆ alkyl which may optionally besubstituted with 1 to 3 groups selected from the group consisting of (i)carbamoyl, (ii) mono- or di-C₁ to C₆ alkylcarbamoyl, (iii) mono- ordi-C₆ to C₁₂ arylcarbamoyl, (iv) mono- or di-C₁ to C₁₀heteroarylcarbamoyl, (v) N—C₁ to C₆ alkyl-N—C₆ to C₁₂ arylcarbamoyl,(vi) N—C₁ to C₆ alkyl-N—C₁ to C₁₀ heteroarylcarbamoyl, (vii) mono- ordi-C₇ to C₁₆ aralkylcarbamoyl, (viii) mono- or di-C₁ to C₁₀heteroaryl-C₁ to C₆ alkylcarbamoyl, (ix) carboxyl, and (x) C₁ to C₆alkoxycarbonyl.
 27. A method of producing a compound or a solvatethereof having the formula of

wherein Ar indicates (1) a C₆ to C₁₄ aromatic hydrocarbon group, (2) a5- to 8-membered aromatic heterocyclic group including 1 to 4 heteroatoms selected from a nitrogen atom, sulfur atom and oxygen atom, otherthan a carbon atom, or (3) a bicyclic or tricyclic aromatic group formedby condensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon ring, wherein the groups (1) to (3) of the above Armay optionally be substituted with any 1 to 5 groups selected from thegroup consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C₁to C₆ alkyl which may optionally be substituted with 1 to 3 halogenatoms, (v) C₂ to C₆ alkenyl which may optionally be substituted with 1to 3 halogen atoms, (vi) C₂ to C₆ alkynyl which may optionally besubstituted with 1 to 3 halogen atoms, (vii) C₃ to C₆ cycloalkyl, (viii)hydroxyl, (ix) C₁ to C₆ alkoxy which may optionally be substituted with1 to 3 groups selected from a halogen atom, mono- or di-C₁ to C₆alkylamino, C₁ to C₆ alkoxy, mono- or di-C₁ to C₆ alkylcarbamoyl, mono-or di-C₇ to C₁₆ aralkylcarbamoyl, mono- or di-C₁ to C₁₀ heteroaryl-C₁ toC₆ alkylcarbamoyl, carboxyl, and C₁ to C₆ alkoxycarbonyl, (x) C₁ toC_(s) alkylenedioxy, (xi) C₁ to C₆ alkylthio which may optionally besubstituted with 1 to 3 groups selected from a halogen atom, mono- ordi-C₁ to C₆ alkylamino, C₁ to C₆ alkoxy, mono- or di-C₁ to C₆alkylcarbamoyl, mono- or di-C₇ to C₁₆ aralkylcarbamoyl, mono- or di-C₁to C₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl, carboxyl and C₁ to C₆alkoxy-carbonyl, (xii) amino, (xiii) mono-C₁ to C₆ alkylamino, (xiv)di-C₁ to C₆ alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C₁ toC₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁ to C₆ alkoxycarbonyl,(xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C₁ to C₆ alkylcarbamoyl,(xxii) di-C₁ to C₆ alkylcarbamoyl, (xxiii) 5- to 6-membered cyclicaminocarbonyl, (xxiv) sulfo, (xxv) C₁ to C₆ alkylsulfonyl, (xxvi) C₁ toC₆ alkoxycarbonylamino, (xxvii) C₁ to C₆ alkylcarbonylamino, (xxviii)mono- or di-C₁ to C₆ alkylaminocarbonylamino, (xxix) aminosulfonyl, and(xxx) mono- or di-C₁ to C₆ alkylaminosulfonyl; X indicates (1) a bond,(2) linear or branched C₁ to C₆ alkylene, (3) an oxygen atom, (4) NR¹³,wherein R¹³ indicates a hydrogen atom or a C₁ to C₆ alkyl group, or (5)—S(O)_(m)— wherein m indicates an integer of 0 to 2; R¹ indicates (1) ahydrogen atom, (2) a halogen atom, or (3) C₁ to C₆ alkyl, or R¹ forms—CH═ together with X; R² and R³ are independently (1) a hydrogen atom,(2) a halogen atom, or (3) C₁ to C₆ alkyl; R⁵ and R⁶ are independently(1) a hydrogen atom or (2) C₁ to C₆ alkyl which may optionally besubstituted with a group selected from the group consisting of (i)carboxyl, (ii) to C₆ alkoxy, (iii) C₁ to C₆ alkoxycarbonyl, (iv) C₆ toC₁₂ aryloxycarbonyl, (v) C₁ to C₁₀ heteroaryloxycarbonyl, and (vi)amino; R² and R³ and also R⁵ and R⁶ may independently form a 3- to8-membered ring; P indicates a protective group selected from the groupconsisting of (1) allyl, (2) allyloxycarbonyl, (3)9-fluorenylmethylcarbonyl, (4) C₁ to C₆ alkyloxycarbonyl which mayoptionally be substituted with 1 to 3 halogen atoms, (5) C₁ to C₆alkylcarbonyl which may optionally be substituted with 1 to 3 halogenatoms, (6) C₇ to C₁₆ aralkyl which may optionally be substituted with 1to 3 groups selected from (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii)C₁ to C₆ alkoxy, and (iv) nitro, (7) C₅ to C₁₆ arylcarbonyl which mayoptionally be substituted with 1 to 3 groups selected from (i) a halogenatom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxy, and (iv) nitro, (8) C₇to C₁₆ aralkyloxycarbonyl which may optionally be substituted with 1 to3 groups selected from (i) a halogen atom, (ii) C₁ to C₆ alkyl, (iii) C₁to C₆ alkoxy, and (iv) nitro, or (9) C₅ to C₁₆ arylsulfonyl which mayoptionally be substituted with 1 to 3 groups selected from (i) a halogenatom, (ii) C₁ to C₆ alkyl, (iii) C₁ to C₆ alkoxyl, and (iv) nitro, orR⁴, wherein R⁴ indicates a (1) a hydrogen atom, (2) C₁ to C₆alkylcarbamoyl, or (3) C₁ to C₆ alkyl which may optionally besubstituted with 1 to 3 groups selected from the group consisting of (i)carbamoyl, (ii) mono- or di-C₁ to C₆ alkylcarbamoyl, (iii) mono- ordi-C₆ to C₁₂ arylcarbamoyl, (iv) mono- or di-C₁ to C₁₀heteroarylcarbamoyl, (v) N—C₁ to C₆ alkyl-N—C₆ to C₁₂ arylcarbamoyl,(vi) N—C₁ to C₆ alkyl-N—C₁ to C₁₀ heteroarylcarbamoyl, (vii) mono- ordi-C₇ to C₁₆ aralkylcarbamoyl, (viii) mono- or di-C₁ to C₁₀heteroaryl-C₁ to C₆ alkylcarbamoyl, (ix) carboxyl, and (x) C₁ to C₆alkoxycarbonyl; W indicates (1) a hydrogen atom, (2) a C₆ to C₁₄aromatic hydrocarbon group, (3) a 5- to 8-membered aromatic heterocyclicgroup including 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom, and an oxygen atom, other than a carbon atom, (4) abicyclic or tricyclic aromatic group formed by condensation of the abovearomatic heterocyclic group and a C₆ to C₁₄ aromatic hydrocarbon ring,and (5) C₁ to C₆ alkyl, or (6) a 5- to 7-membered heterocycloalkyl groupwhich may optionally be substituted with 1 to 3 groups selected from oxoand phenyl, wherein each of the groups (2) to (4) of the above W mayoptionally be substituted with 1 to 5 groups selected from the groupconsisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C₁ to C₆alkyl which may optionally be substituted with a halogen atom, amino, C₁to C₆ alkoxycarbonyl, C₁ to C₆ alkoxycarbonylamino, and carboxyl, (v) C₂to C₆ alkenyl which may optionally be substituted with 1 to 3 halogenatoms, (vi) C₂ to C₆ alkynyl which may optionally be substituted with 1to 3 halogen atoms, (vii) C₃ to C₆ cycloalkyl, (viii) hydroxyl, (ix) C₁to C₆ alkoxy which may optionally be substituted with 1 to 3 groupsselected from a halogen atom, hydroxyl, C₁ to C₆ alkoxy, amino, andmono- or di-C₁ to C₆ alkylamino, (x) C₁ to C₅ alkylenedioxy, (xi) C₁ toC₆ alkylthio which may optionally be substituted with 1 to 3 groupsselected from a halogen atom, hydroxyl, C₁ to C₆ alkoxy, amino, andmono- or di-C₁ to C₆ alkylamino, (xii) amino, (xiii) mono-C₁ to C₆alkylamino, (xiv) di-C₁ to C₆ alkylamino, (xv) 5- to 6-membered cyclicamino, (xvi) C₁ to C₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁ to C₆alkoxycarbonyl which may optionally be substituted with a halogen atom,(xix) C₇ to C₁₆ aralkyloxycarbonyl which may optionally be substitutedwith a halogen atom, (xx) carbamoyl, (xxi) mono-C₁ to C₆ alkylcarbamoylwhich may optionally be substituted with 1 to 3 groups selected from ahalogen atom, hydroxyl, carboxyl, C₁ to C₆ alkoxy, amino, and mono- ordi-C₁ to C₆ alkylamino, (xxii) di-C₁ to C₆ alkylcarbamoyl which mayoptionally be substituted with hydroxyl, (xxiii) 5- to 6-membered cyclicaminocarbonyl which may optionally be substituted with C₁ to C₆alkoxycarbonyl, (xxiv) C₆ to C₁₀ arylcarbamoyl, (xxv) C₁ to C₁₀heteroarylcarbamoyl, (xxvi) C₇ to C₁₆ aralkylcarbamoyl, (xxvii) C₁ toC₁₀ heteroaryl-C₁ to C₆ alkylcarbamoyl, (xxviii) N—C₁ to C₆ alkyl-N—C₆to C₁₂ arylcarbamoyl, (xxix) C₃ to C₆ cycloalkylcarbamoyl, (xxx) sulfo,(xxxi) C₁ to C₆ alkylsulfonyl, (xxxii) C₁ to C₆ alkylsulfonylamino,(xxxiii) C₆ to C₁₂ arylsulfonylamino which may optionally be substitutedwith C₁ to C₆ alkyl, (xxxiv) C₁ to C₁₀ heteroarylsulfonylamino, (xxxv)C₁ to C₆ alkoxycarbonylamino, (xxxvi) C₁ to C₆ alkylcarbonylamino,(xxxvii) mono- or di-C₁ to C₆ alkylaminocarbonylamino, (xxxviii) C₆ toC₁₂ aryl, (xxxix) C₁ to C₁₀ heteroaryl, (xl) C₆ to C₁₀ aryloxy, (xli) C₁to C₁₀ heteroaryloxy, (xlii) C₇ to C₁₆ aralkyloxy, (xliii) C₁ to C₁₀heteroaryl-C₁ to C₆ alkyloxy, (xliv) aminosulfonyl, (xlv) mono- or di-C₁to C₆ alkylaminosulfonyl, (xlvi) C₇ to C₁₆ aralkyloxycarbamoyl, and(xlvii) C₁ to C₁₀ heteroaryl-C₁ to C₆ alkyloxycarbamoyl; and Z indicates(1) a bond or (2) CR⁷R⁸ wherein R⁷ and R⁸ are, independently, (A) ahydrogen atom, (B) C₁ to C₆ alkyl which may optionally be substitutedwith 1 to 5 groups selected from the group consisting of (i) carboxyl,(ii) C₁ to C₆ alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl, (v) C₁ to C₆alkoxy, and (vi) a halogen atom, (C) C₆ to C₁₂ aryl or C₁ to C₁₀heteroaryl, which may optionally be substituted with 1 to 5 groupsselected from the group consisting of (i) a halogen atom and (ii) analkyl group which may optionally be substituted with 1 to 3 halogenatoms, (D) C₃ to C₆ cycloalkyl which may optionally be substituted with1 to 5 groups selected from (i) a halogen atom and (ii) an alkyl groupwhich may optionally be substituted with 1 to 3 halogen atoms, (E)—COOR^(S) wherein R⁹ indicates a hydrogen atom or C₁ to C₆ alkyl, or (F)CONR¹⁰R¹¹ wherein R¹⁰ and R¹¹ are, independently, (a) a hydrogen atom,(b) C₁ to C₆ alkyl which may optionally be substituted with 1 to 3groups selected from the group consisting of (i) a halogen atom, (ii) C₃to C₆ cycloalkyl, (iii) carboxyl, (iv) C₁ to C₆ alkoxycarbonyl, (v) C₁to C₆ alkylcarbonyl, (vi) carbamoyl, (vii) mono-C₁ to C₆ alkylcarbamoyl,(viii) di-C₁ to C₆ alkylcarbamoyl, (ix) C₆ to C₁₂ aryl, and (x) C₁ toC₁₀ heteroaryl, (c) OR¹² wherein R¹² indicates a hydrogen atom or C₁ toC₆ alkyl, or (d) (1) a C₆ to C₁₄ aromatic hydrocarbon group, (2) a 5- to8-membered aromatic heterocyclic group including 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom, and an oxygen atom, otherthan a carbon atom, or (3) a bicyclic or tricyclic aromatic group formedby condensation of the above aromatic heterocyclic group and a C₆ to C₁₄aromatic hydrocarbon ring, wherein each of the groups (1) to (3) mayoptionally be substituted with 1 to 5 groups selected from the groupconsisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C₁ to C₆alkyl which may optionally be substituted with 1 to 3 halogen atoms, (v)C₂ to C₆ alkenyl which may optionally be substituted with 1 to 3 halogenatoms, (vi) C₂ to C₆ alkynyl which may optionally be substituted with 1to 3 halogen atoms, (vii) C₃ to C₆ cycloalkyl, (viii) hydroxyl, (ix) C₁to C₆ alkoxy which may optionally be substituted with 1 to 3 halogenatoms, (x) C₁ to C₅ alkylenedioxy, (xi) C₁ to C₆ alkylthio which mayoptionally be substituted with 1 to 3 halogen atoms, (xii) amino, (xiii)mono-C₁ to C₆ alkylamino, (xiv) di-C₁ to C₆ alkylamino, (xv) 5- to6-membered cyclic amino, (xvi) C₁ to C₆ alkylcarbonyl, (xvii) carboxyl,(xviii) C₁ to C₆ alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl,(xxi) mono-C₁ to C₆ alkylcarbamoyl, (xxii) di-C₁ to C₆ alkylcarbamoyl,(xxiii) C₆ to C₁₀ arylcarbamoyl, (xxiv) C₁ to C₁₀ heteroarylcarbamoyl,(xxv) sulfo, (xxvi) C₁ to C₆ alkylsulfonyl, (xxvii) aminosulfonyl, and(xxviii) mono- or di-C₁ to C₆ alkylaminosulfonyl; comprising undergoinga coupling reaction of the compound or a salt thereof having the formula(III):

with the compound or a salt thereof having the formula (IV)

wherein Q² and Q³ independently indicate C₆ to C₁₀ aryloxy group whichmay optionally be substituted with 1 to 3 halogen atoms or nitro, or ahalogen atom, and Y′ indicates —S(O)_(n)— (wherein n indicates aninteger of 1 or 2) or C(═O), and the compound or salt thereof having theformula (V)